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Results for “Homologous Recombination Deficiency”

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PubMed2026

Patient-derived organoids predict responses to chemotherapy and PARP inhibitors in advanced ovarian cancer.

BACKGROUND: While tumor organoids hold promise for personalized medicine, clinical validation of epithelial ovarian cancer (EOC) organoids as predictors of therapeutic efficacy-particularly for PARP inhibitors (PARPi)-remains unestablished. METHODS: Patient-derived organoids (PDOs) were established from treatment-naive EOC specimens and characterized by H&E staining, immunohistochemistry, and whole-exome sequencing. Drug sensitivity testing (DST) was performed using carboplatin, paclitaxel, and PARPi (olaparib and niraparib). Clinical homologous recombination deficiency (HRD) status was assessed by tumor sequencing. Organoid responses were prospectively compared to patient outcomes after first-line chemotherapy (carboplatin/paclitaxel) and PARPi maintenance. RESULTS: PDOs were successfully established from 21 of 30 patients (70%) across multiple EOC subtypes and preserved the histopathological features and genomic landscapes of their corresponding primary tumors. Organoid-based DST accurately predicted responses to first-line carboplatin/paclitaxel, with a sensitivity of 100% (95% CI 62.88-100%), specificity of 66.67% (95% CI 12.53-98.23%), accuracy of 91.67% (95% CI 61.52-99.79%), AUC of 0.95 (95% CI 0.85-1.00), and Cohen's kappa of 0.75 (95% CI 0.30-1.00). In evaluating PARPi response, organoids revealed discrepancies between genomic HRD status and actual drug responses. One HRD-positive PDO was PARPi-resistant, consistent with patient non-response, while two HRR-proficient PDOs showed PARPi sensitivity and corresponding clinical benefit. CONCLUSIONS: EOC-derived PDOs provide a robust platform for predicting chemotherapy response and offer added value in assessing PARPi efficacy beyond genomic profiling. Combination of organoid-based testing with genomic analysis may improve precision treatment strategies in EOC.

Humans↗

PubMed2024

Activated NAD+ biosynthesis pathway induces olaparib resistance in BRCA1 knockout pancreatic cancer cells.

PARP inhibitors have been developed as anti-cancer agents based on synthetic lethality in homologous recombination deficient cancer cells. However, resistance to PARP inhibitors such as olaparib remains a problem in clinical use, and the mechanisms of resistance are not fully understood. To investigate mechanisms of PARP inhibitor resistance, we established a BRCA1 knockout clone derived from the pancreatic cancer MIA PaCa-2 cells, which we termed C1 cells, and subsequently isolated an olaparib-resistant C1/OLA cells. We then performed RNA-sequencing and pathway analysis on olaparib-treated C1 and C1/OLA cells. Our results revealed activation of cell signaling pathway related to NAD+ metabolism in the olaparib-resistant C1/OLA cells, with increased expression of genes encoding the NAD+ biosynthetic enzymes NAMPT and NMNAT2. Moreover, intracellular NAD+ levels were significantly higher in C1/OLA cells than in the non-olaparib-resistant C1 cells. Upregulation of intracellular NAD+ levels by the addition of nicotinamide also induced resistance to olaparib and talazoparib in C1 cells. Taken together, our findings suggest that upregulation of intracellular NAD+ is one of the factors underlying the acquisition of PARP inhibitor resistance.

Humans↗

PubMed2026

Clinical relevance of HRD score in pheochromocytomas and paragangliomas: molecular cluster distribution and prognostic implications.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors with variable metastatic potential across molecular clusters. While the homologous recombination deficiency (HRD) score has been established as a surrogate for HRD-related genomic instability to guide prognostic evaluation and therapeutic options in multiple solid tumors, its relevance in PPGLs remains unexplored. Here, data from 133 PPGL patients in the TCGA database were extracted to assess relationships between the HRD score and molecular clusters, metastasis, metastasis-free survival (MFS), and other clinical characteristics. Subsequently, a real-world cohort of 54 matched blood-tumor pairs was subjected to whole-exome sequencing, with HRD scores calculated to confirm the prior observations. The median HRD score was 7.0 and 9.0 in the TCGA-PPGL dataset and the clinical cohort, respectively. In the TCGA dataset, an elevated HRD score significantly correlated with metanephrine secretion, C2 cluster, and metastasis. Multivariate analysis identified a higher HRD score as an independent risk factor for shorter MFS (HR = 1.33, P = 0.008). Patients with HRD scores ≥ 7 exhibited significantly shorter MFS (P = 0.037), which was observed exclusively within the C1A cluster (P = 0.007). Analyses of our clinical validation cohort corroborated this cluster-specific distribution and further revealed higher HRD scores in three temozolomide-treated PPGLs compared with those treatment-naive C1A tumors (P = 0.043). In conclusion, despite exhibiting lower levels in C1A clusters, an elevated HRD score emerges as a promising indicator for refined metastatic risk stratification in PPGLs. Futhermore, the substantial increase in HRD score following temozolomide treatment provides a rationale for PARP inhibitor sequential or combination therapy in metastatic PPGLs.

Humans↗

PubMed2026

An overview of the DNA damage response in female reproductive system and breast cancers: A narrative review.

The DNA damage response (DDR) is a fundamental cellular network that preserves genomic integrity, and its dysregulation drives initiation, progression, and therapeutic response in female reproductive system and breast cancers. This narrative review provides a comparative analysis of DDR alterations across ovarian, endometrial, cervical, and breast cancers, synthesizing molecular studies, clinical trials, and international guidelines from PubMed/MEDLINE, Scopus, and Web of Science. DDR alterations vary substantially among these cancers, reflecting differences in tissue origin, hormonal regulation, and viral oncogenesis. Homologous recombination repair defects, particularly in breast cancer susceptibility 1/2, partner and localizer of BRCA2, ataxia telangiectasia mutated, and checkpoint kinase 2), are prevalent in ovarian, endometrial, and breast cancers, predicting sensitivity to platinum-based chemotherapy and poly (ADP-ribose) polymerase inhibitors. In endometrial cancer, homologous recombination deficiency predominates in high-grade tumor protein p53-mutated subtypes, while Fanconi anemia pathway alterations characterize aggressive serous carcinomas. Cervical cancer exhibits virus-induced DDR disruption and replication stress. Quantitative biomarkers, including tumor mutational burden, microsatellite instability, Radiation sensitive 51, Fanconi anemia complementation group D2, excision repair cross-complementation group 1, and DDR-related microRNAs enable patient stratification. Emerging ataxia telangiectasia and Rad3-related and WEE1 inhibitors show promise in combination regimens. Understanding of tumor-specific DDR enables rational therapeutic stratification, providing a framework for precision oncology.

DNA damage response, Ovarian neoplasms, Endometria↗

PubMed2026

Molecular differences between poorly and well/moderately differentiated lung adenocarcinoma and their clinical implications.

BACKGROUND: Diagnostic and therapeutic techniques for lung adenocarcinoma (LUAD) have advanced rapidly. However, the morphology-based assessment of tumor differentiation commonly used in clinical practice has several limitations, including strong subjectivity, inability to reflect tumor heterogeneity, and limited prognostic predictive value. This study aimed to identify key genetic mutations associated with tumor differentiation features and explored their potential clinical impact of these molecular features on tumor prognosis and therapeutic response. METHODS: In this study, 196 LUAD tissue samples collected from Fujian Cancer Hospital between 2021 and 2023 were analyzed using integrated high-throughput sequencing and comprehensive bioinformatics approaches. Molecular differences between poorly differentiated tumors and moderately/well-differentiated tumors were characterized. The effects of these molecular alterations on tumor behavior and therapeutic response were examined, with the aim of exploring biomarkers associated with poor prognosis and treatment in LUAD. RESULTS: Our findings showed a significant quantitative difference in tumor mutation burden, EGFR co-mutations, patterns of co-occurrence resulting in distinct clinical outcomes. Among these alterations, mutations in LRP1B and TP53, as well as EGFR amplification, MET amplification, JAK2 deletion and CDKN2B deletion were significantly enriched in the poorly differentiated group, whereas EGFR mutations were significantly enriched in the moderately/well-differentiated group. We also identified MET amplification and LRP1B mutation as independent poor prognostic factors in LUAD. Moreover, a subset of poorly differentiated group exhibited DNA double-strand breaks possibly due to homologous recombination deficiency (HRD), along with frequent alterations of immune evasion-related genes. CONCLUSIONS: These findings provide novel insights into the molecular basis of LUAD and the development of novel targeted differentiation-related therapies and precision genome-guided treatments.

Lung adenocarcinoma (LUAD)↗

PubMed2026

Systemic treatment of advanced pancreatic cancer: A Comprehensive Review.

IMPORTANCE: Pancreatic adenocarcinoma (PDAC) is an uncommon but potentially catastrophic diagnosis with historically poor prognosis. It is the tenth most prevalent cancer in the US & UK. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide, with a five-year survival rate of approximately 10%. Despite increasing understanding of its molecular biology, systemic treatment options for advanced disease remain limited, and survival outcomes have improved only modestly over the past decade. OBSERVATIONS: This narrative review traces the evolution of systemic therapy for advanced PDAC from gemcitabine monotherapy through the landmark FOLFIRINOX (PRODIGE trial) and gemcitabine/nab-paclitaxel (MPACT trial) combination regimens, which remain the standard of care. Second-line options including liposomal irinotecan plus 5-FU/LV (NAPOLI-1) and maintenance olaparib for germline BRCA1/2-mutated disease (POLO) are also reviewed. Emerging data on sequential treatment strategies (SEQUENCE trial), biomarker-driven treatment selection (PRIMUS-001, PASS-01), and precision medicine approaches targeting actionable molecular subgroups, including dMMR/MSI-H, NTRK fusions, and homologous recombination deficiency are discussed. Real-world evidence comparing FOLFIRINOX and gemcitabine/nab-paclitaxel is critically appraised, including the challenges of patient selection, tolerance, and applicability outside clinical trial settings. CONCLUSION AND RELEVANCE: Despite incremental progress, the treatment landscape of advanced PDAC remains challenging. Molecular stratification and biomarker-driven precision oncology represent the most promising path forward. This review serves as a clinical reference for physicians managing advanced pancreatic cancer, highlighting current evidence, evidence limitations, and future research priorities including prospective biomarker-driven trials and improved access to genomic testing.

Biomarkers↗

PubMed2003

Caffeine could not efficiently sensitize homologous recombination repair-deficient cells to ionizing radiation-induced killing.

Caffeine inhibits ATM and ATR, two important checkpoint regulators, abolishes ionizing radiation-induced checkpoint response, and radiosensitizes cells. Radiation-induced DNA double-strand breaks (DSBs) are repaired by two major processes, homologous recombination repair (HRR) and nonhomologous end joining (NHEJ). It remains unclear which repair process, HRR or NHEJ, is affected when the checkpoint responses are abolished by caffeine. In this study we observed the effect of caffeine on gene-targeted DT40 chicken lymphoblast cells. We show that caffeine efficiently abolishes S- and G(2)-phase checkpoint responses after irradiation in all cell lines tested and greatly radiosensitizes wild-type and ATM(-/-) cells, the partially checkpoint-deficient cells. However, caffeine has a much smaller radiosensitizing effect on RAD54(-/-) cells and has no effect on RAD51-deficient cells. RAD51 and RAD54 are the important factors for HRR. Our results indicate that the checkpoint responses abolished by caffeine (S and G(2)) mainly affect HRR, which results in cell radiosensitization.

Animals↗

PubMed2001

Involvement of nucleotide excision repair in a recombination-independent and error-prone pathway of DNA interstrand cross-link repair.

DNA interstrand cross-links (ICLs) block the strand separation necessary for essential DNA functions such as transcription and replication and, hence, represent an important class of DNA lesion. Since both strands of the double helix are affected in cross-linked DNA, it is likely that conservative recombination using undamaged homologous regions as a donor may be required to repair ICLs in an error-free manner. However, in Escherichia coli and yeast, recombination-independent mechanisms of ICL repair have been identified in addition to recombinational repair pathways. To study the repair mechanisms of interstrand cross-links in mammalian cells, we developed an in vivo reactivation assay to examine the removal of interstrand cross-links in cultured cells. A site-specific psoralen cross-link was placed between the promoter and the coding region to inactivate the expression of green fluorescent protein or luciferase genes from reporter plasmids. By monitoring the reactivation of the reporter gene, we showed that a single defined psoralen cross-link was removed in repair-proficient cells in the absence of undamaged homologous sequences, suggesting the existence of an ICL repair pathway that is independent of homologous recombination. Mutant cell lines deficient in the nucleotide excision repair pathway were examined and found to be highly defective in the recombination-independent repair of ICLs, while mutants deficient in homologous recombination were found to be proficient. Mutation analysis of plasmids recovered from transfected cells showed frequent base substitutions at or near positions opposing a cross-linked thymidine residue. Based on these results, we suggest a distinct pathway for DNA interstrand cross-link repair involving nucleotide excision repair and a putative lesion bypass mechanism.

Animals↗

PubMed1993

Plasminogen activator inhibitor-1 gene-deficient mice. I. Generation by homologous recombination and characterization.

Homozygous plasminogen activator inhibitor-1 (PAI-1)-deficient (PAI-1-/-) mice were generated by homologous recombination in D3 embryonic stem cells. Deletion of the genomic sequences encompassing the transcription initiation site and the entire coding regions of murine PAI-1 was demonstrated by Southern blot analysis. A 3.0-kb PAI-1-specific mRNA was identified by Northern blot analysis in liver from PAI-1 wild type (PAI-1+/+) but not from PAI-1-/- mice. Plasma PAI-1 levels, measured 2-4 h after endotoxin (2.0 mg/kg) injection were 63 +/- 2 ng/ml, 30 +/- 10 ng/ml, and undetectable (< 2 ng/ml) in PAI-1+/+, heterozygous (PAI-1+/-) and PAI-1-/- mice, respectively (mean +/- SEM, n = 4-11). PAI-1-specific immunoreactivity was demonstrable in kidneys of PAI-1+/+ but not of PAI-1-/- mice. SDS-gel electrophoresis of plasma incubated with 125I-labeled recombinant human tissue-type plasminogen activator revealed an approximately 115,000-M(r) component with plasma from endotoxin-stimulated (0.5 mg/kg) PAI-1+/+ but not from PAI-1-/- mice, which could be precipitated with a polyclonal anti-PAI-1 antiserum. PAI-1-/- mice were viable, produced similar sizes of litters as PAI-1+/+ mice, and showed no apparent macroscopic or microscopic histological abnormalities.

Animals↗

PubMed1996

Absence of UV-induced non-homologous recombination in repair-deficient CHO cell lines transfected with ERCC genes.

The nucleotide excision repair pathway removes a broad spectrum of DNA lesions, including UV-induced damage. To ascertain whether the repair of the latter has a causative role in the enhancement of non-homologous recombination, Chinese hamster CHO cell lines proficient and deficient in the ability to repair UV-induced damage were transfected with a plasmid containing the bacterial neoR gene. Following UV-treatment an enhancement of non-homologous recombination above the spontaneous level was observed in repair-proficient cells, whereas no increase was observed in repair-deficient cell lines. Hence, the latter were transfected with the corresponding excision repair cross complementing human genes and the resulting repair-proficient transfectants were tested for UV-induced non-homologous recombination. In both untreated and UV-treated transfectants, the frequencies of the event were not significantly different. Cumulatively, the results suggest that non-homologous recombination induced by UV-irradiation is not restored by the correction of the excision repair defect.

Animals↗

PubMed2004

Ku86 deficiency leads to reduced intrachromosomal homologous recombination in vivo in mice.

Ku70 and Ku86 together with DNA-PKcs form the DNA-dependent protein kinase (DNA-PK) complex that is involved in DNA double-strand break repair by nonhomologous end joining. We investigated the effect of Ku86 mutation on intrachromosomal homologous recombination (HR) resulting in deletions in vivo in mice. We quantified such deletion events using a phenotypic pigmentation assay. Deletion of one copy of a 70 kb DNA duplication in the pink-eyed unstable (pun) allele results in reversion to the wildtype pink-eyed dilution (p) gene, allowing black pigment accumulation in cells of the retinal pigment epithelium (RPE). We found that the frequency of homologous recombination was significantly reduced in Ku86 deficient mice. Furthermore, the proliferation of cells in which recombination events occurred was reduced and developmentally delayed in the Ku86 deficient mice. These data indicate a role for Ku86 directly or indirectly in homologous recombination in vivo.

Animals↗

PubMed2004

Yeast MPH1 gene functions in an error-free DNA damage bypass pathway that requires genes from Homologous recombination, but not from postreplicative repair.

The MPH1 gene from Saccharomyces cerevisiae, encoding a member of the DEAH family of proteins, had been identified by virtue of the spontaneous mutator phenotype of respective deletion mutants. Genetic analysis suggested that MPH1 functions in a previously uncharacterized DNA repair pathway that protects the cells from damage-induced mutations. We have now analyzed genetic interactions of mph1 with a variety of mutants from different repair systems with respect to spontaneous mutation rates and sensitivities to different DNA-damaging agents. The dependence of the mph1 mutator phenotype on REV3 and REV1 and the synergy with mutations in base and nucleotide excision repair suggest an involvement of MPH1 in error-free bypass of lesions. However, although we observed an unexpected partial suppression of the mph1 mutator phenotype by rad5, genetic interactions with other mutations in postreplicative repair imply that MPH1 does not belong to this pathway. Instead, mutations from the homologous recombination pathway were found to be epistatic to mph1 with respect to both spontaneous mutation rates and damage sensitivities. Determination of spontaneous mitotic recombination rates demonstrated that mph1 mutants are not deficient in homologous recombination. On the contrary, in an sgs1 background we found a pronounced hyperrecombination phenotype. Thus, we propose that MPH1 is involved in a branch of homologous recombination that is specifically dedicated to error-free bypass.

4-Nitroquinoline-1-oxide↗

PubMed1995

Studies on the metabolism of retinol and retinol-binding protein in transthyretin-deficient mice produced by homologous recombination.

Tissue needs for retinoids are believed to be satisfied through the delivery in the circulation of retinol by its specific plasma transport protein, retinol-binding protein (RBP), which circulates as a 1-to-1 protein complex with transthyretin (TTR). The binding of RBP to TTR is thought to prevent filtration of retinol-RBP in the kidney and to play a role in secretion of RBP from hepatocytes. Recently a strain of mice (TTR-) that totally lacks immunoreactive TTR was produced by targeted mutagenesis. We have explored the effects of TTR deficiency on retinol and RBP metabolism in this mutant strain. In pooled plasma from the TTR- mice retinol levels averaged 6% of those of wild type animals. Similarly, plasma RBP in the TTR- mice was found to be 5% of wild type levels. Hepatic retinol and retinyl ester levels were similar for mutant and wild type mice, suggesting that the mutation affects neither the uptake nor storage of dietary retinol. Levels of retinol and retinyl esters in testis, kidney, spleen, and eye cups from TTR- mice were normal. Plasma all-trans-retinoic acid levels for the TTR- mice were 2.3-fold higher than those of wild type (425 versus 190 ng/dl). Kidney RBP levels were similar for the mutant and wild type mice and we were unable to detect intact RBP in urine from TTR- mice. Hepatic RBP levels in the TTR- mice were 60% higher than those of wild type mice (39.8 versus 25.0 micrograms of RBP/g of tissue). These data may suggest that there is a partial blockage in RBP secretion from TTR- hepatocytes that leads to lessened plasma levels of retinol-RBP.

Animals↗

PubMed2004

RecBCD enzyme overproduction impairs DNA repair and homologous recombination in Escherichia coli.

The Escherichia coli RecBCD enzyme is a powerful helicase and nuclease that processes DNA molecules containing blunt double-strand DNA end. Mutants deprived of RecBCD enzyme functions are extremely sensitive to DNA-damaging agents, poorly viable and severely deficient in homologous recombination. Remarkably, such important cellular functions rely on only about 10 molecules of RecBCD present in a cell. To determine the effect of an increased concentration of RecBCD enzyme and its derivatives on cellular processes that depend on the enzyme, we introduced wild-type and mutant alleles of recBCD genes on a low-copy-number plasmid into recB and wild-type bacteria and assessed their capacity for DNA repair and homologous recombination. We found that the overproduction of RecBCD enzyme, as well as RecBC and their nuclease-deficient derivatives, impairs both DNA repair and homologous recombination in E. coli. We also show that chromosomal degradation was increased in gamma-irradiated bacteria overproducing RecBCD but not in those overproducing RecBC enzyme, indicating that the increased nuclease activity is not the reason for defective DNA repair and homologous recombination observed in those cells. Our collective results suggest that DNA binding and processive helicase activities of the overproduced RecBCD enzyme, or its derivates, impair DNA repair and homologous recombination in E. coli. The cells control these activities of RecBCD by maintaining its extremely low concentration, thereby allowing efficient DNA repair and homologous recombination.

Conjugation, Genetic↗

PubMed1993

Two cDNAs from the plant Arabidopsis thaliana that partially restore recombination proficiency and DNA-damage resistance to E. coli mutants lacking recombination-intermediate-resolution activities.

Escherichia coli ruvC recG mutants lack RuvC endonuclease, which resolves crossed-strand joint molecules (Holliday junctions) formed during homologous recombination into recombinant products, and an activity (RecG) thought to partially replace RuvC. They are therefore highly deficient in homologous recombination, and sensitive to UV light and chemical DNA-damaging agents, presumably because of inability to tolerate unrepaired DNA damage by recombinational mechanisms (Lloyd, R.G. (1991) J. Bacteriol. 173:5414-5418). We transformed these mutants with plasmids expressing cDNAs from the plant Arabidopsis thaliana. Selection for bacteria with increased resistance to methylmethanesulfonate yielded two cDNAs, designated DRT111 and DRT112 (DNA-damage-repair/toleration). Expression of these plant cDNAs, especially DRT111, restored conjugal recombination proficiencies in ruvC and ruvC recG mutants to nearly wild-type levels. Both plant cDNAs significantly increased resistance of both mutants to UV light and several chemical DNA-damaging agents, but did not fully correct the mutant phenotypes. Drt111 activity, but not Drt112, also increased, to nearly wild-type levels, resistance of recG single mutants to UV plus mitomycin C. The predicted Drt111 and Drt112 polypeptides, 383 and 167 amino acids respectively, show no similarity with one another or with prokaryotic Holliday resolvases. Both appear chloroplast targeted; Drt112 is highly homologous to Arabidopsis plastocyanin. DRT111 and DRT112 probes hybridize only to DNA from closely related plants.

Arabidopsis↗

PubMed1999

Involvement of p53 in X-ray induced intrachromosomal recombination in mice.

The tumor suppressor gene Trp53 (also known as p53) is the most frequently mutated gene in human cancers. p53 is induced in response to DNA damage and effects a G(1) cell cycle arrest. It is believed that p53 plays a key role in maintaining genomic integrity following exposure to DNA-damaging agents. We determined the frequency of spontaneous and DNA damage-induced homologous intrachromosomal recombination in p53-deficient mouse embryos. Homologous intrachromosomal recombination events resulting in deletions at the pink eyed unstable (p(un)) locus result in reversion to the p gene. Reversions occurring in embryonic premelanocytes give rise to black spots on the gray fur of the offspring. Pregnant C57BL/6J p(un)/p(un) p53(+/-) mice were exposed to X-rays (1 Gy) or administered benzo¿apyrene (B¿aP; 30 or 150 mg/kg i.p.) 10 days after conception. Frequencies of spontaneous p(un) reversions in p53(-/-) and p53(+/-) animals were not significantly different compared with their wild-type littermates. X-ray treatment increased the recombination frequency in wild-type and p53(+/-), but surprisingly not in p53(-/-) offspring. In contrast, B¿aP treatment caused a dose-dependent increase in p(un) reversion frequencies in all three genotypes. Western blot analysis of embryos indicated that p53 protein levels increased approximately 3-fold following X-ray treatment, while B¿aP had no effect on p53 expression. These results are in agreement with the proposal that p53 is involved in the DNA damage response following X-ray exposure and suggest that X-ray-induced double-strand breaks are processed differently in p53(-/-) animals.

Animals↗

PubMed2005

Reduced repair of DNA double-strand breaks by homologous recombination in a DNA ligase I-deficient human cell line.

Genetic and biochemical studies of mammalian DNA ligase I indicate that this multifunctional enzyme plays a key role in the completion of DNA replication and certain DNA excision repair pathways. However, the involvement of DNA ligase I in DNA double-strand break repair has not been examined. Here we have determined the effect of DNA ligase I-deficiency on the frequency of homologous recombination initiated by a site-specific DNA double-strand break. We found that expression of wild-type DNA ligase I in a human DNA ligase I mutant cell line significantly increased the frequency of homologous recombination. Notably, the ability of DNA ligase I to promote the recombinational repair of DNA double-strand breaks was dependent upon its interaction with proliferating cell nuclear antigen. Thus, our results demonstrate that DNA ligase I-deficiency reduces recombinational repair of DNA double-strand breaks.

Cell Line↗

PubMedDate not supplied

Evaluation of adaptive responses to cisplatin in normal and mutant cell lines with mutations in recombination repair pathways.

Cell lines mutant in specific DNA repair pathways were used to determine if these pathways are involved in adaptive responses. For these studies, the effect of deficiencies in homologous recombination repair (HR) were studied in the parental AA8 and mutant (irs)ISF cell line pair and for deficiencies in the nonhomologous endjoining (NHEJ) pathway in the mouse MEF parental and Ku80 mutant cell line pair. The results showed that the XRCC3 mutation in the HR-deficient mutant inhibited adaptive responses to low doses of cisplatin and radiation. The parental lines showed transient adaptive responses to both low-dose cisplatin and radiation treatment. For the mouse MEF and the Ku80 cells, no adaptive responses were observed in either cell line. However, there was an initial transient sensitization response followed by partial recovery. Thus, it appears that the HR repair system may be involved in the adaptive response to cisplatin and radiation. For the NHEJ repair system the question could not be answered since no adaptive responses were evident in the parental line.

Animals↗