Biomedical subjects

Phang-Lang Chen

Publications and source records attributed to Phang-Lang Chen.

17 recordsLinked to original sources

PubMed2006

Removal of BRCA1/CtIP/ZBRK1 repressor complex on ANG1 promoter leads to accelerated mammary tumor growth contributed by prominent vasculature.

BRCA1 exerts transcriptional repression through interaction with CtIP in the C-terminal BRCT domain and ZBRK1 in the central domain. A dozen genes, including angiopoietin-1 (ANG1), a secreted angiogenic factor, are corepressed by BRCA1 and CtIP based on microarray analysis of mammary epithelial cells in 3D culture. BRCA1, CtIP, and ZBRK1 form a complex that coordinately represses ANG1 expression via a ZBRK1 recognition site in the ANG1 promoter. Impairment of this complex upregulates ANG1, which stabilizes endothelial cells that form a capillary-like network structure. Consistently, Brca1-deficient mouse mammary tumors exhibit accelerated growth, pronounced vascularization, and overexpressed ANG1. These results suggest that, besides its role in maintaining genomic stability, BRCA1 directly regulates the expression of angiogenic factors to modulate the tumor microenvironment.

Angiopoietin-1↗

PubMed2005

Depletion of BRCA1 impairs differentiation but enhances proliferation of mammary epithelial cells.

Cumulative evidence indicates that breast cancer-associated gene 1 (BRCA1) participates in DNA damage repair and cell-cycle checkpoint control, serving as a tumor susceptibility gene to maintain the global genomic stability. However, whether BRCA1 has a direct role in cell proliferation and differentiation, two key biological functions in tumorigenesis, remains unclear. Here we demonstrate BRCA1 mediates differentiation of mammary epithelial cell (MEC) for acinus formation by using the in vitro 3D culture system. Reduction of BRCA1 in MEC by RNA interference impairs the acinus formation but enhances proliferation. Such aberrations can be rescued by expression of wild-type BRCA1 as well as a mutant at the RAD50-binding domain but not at the C-terminal BRCT domain, suggesting that the C-terminal BRCT domain has a critical role in these processes. Consistently, depletion of BRCA1 up-regulates the gene expression for proliferation but down-regulates that for differentiation. Moreover, application of the medium conditioned by differentiating normal MEC can reverse the phenotypes of differentiation-defective breast cancer cells bearing reduced BRCA1 functions. Our observation implies BRCA1 is involved in secretion of certain paracrine/autocrine factors that induce MEC differentiation in response to extracellular matrix signals, providing, in part, an explanation for the etiological basis of either sporadic or familial breast cancer due to the loss or reduction of BRCA1.

Adenoviridae↗

PubMed2005

STAT-1 facilitates the ATM activated checkpoint pathway following DNA damage.

STAT-1 plays a role in mediating stress responses to various stimuli and has also been implied to be a tumour suppressor. Here, we report that STAT-1-deficient cells have defects both in intra-S-phase and G2-M checkpoints in response to DNA damage. Interestingly, STAT-1-deficient cells showed reduced Chk2 phosphorylation on threonine 68 (Chk2(-T68)) following DNA damage, suggesting that STAT-1 might function in the ATM-Chk2 pathway. Moreover, the defects in Chk2(-T68) phosphorylation in STAT-1-deficient cells also correlated with reduced degradation of Cdc25A compared with STAT-1-expressing cells after DNA damage. We also show that STAT-1 is required for ATM-dependent phosphorylation of NBS1 and p53 but not for BRCA1 or H2AX phosphorylation following DNA damage. Expression levels of BRCT mediator/adaptor proteins MDC1 and 53BP1, which are required for ATM-mediated pathways, are reduced in cells lacking STAT-1. Enforced expression of MDC1 into STAT-1-deficient cells restored ATM-mediated phosphorylation of downstream substrates. These results imply that STAT-1 plays a crucial role in the DNA-damage-response by regulating the expression of 53BP1 and MDC1, factors known to be important for mediating ATM-dependent checkpoint pathways.

Adaptor Proteins, Signal Transducing↗

PubMed2005

NFBD1/Mdc1 mediates ATR-dependent DNA damage response.

Budding yeast Rad9 (scRad9) plays a central role in mediating Mec1-dependent phosphorylation by recruiting its downstream substrates. The human scRad9 orthologues 53BP1 and NFBD1 associate with ionizing radiation-induced foci (IRIF) at sites of DNA repair. RNAi-based gene silencing of 53BP1 or NFBD1 has shown impaired phosphorylation of SQ/TQ [ataxia-telangiectasia mutated/ATM and Rad3-related (ATM/ATR) substrates] at IRIF, intra-S, and G(2)-M checkpoints and has thereby revealed essential roles for 53BP1 and NFBD1 in the DNA damage signaling pathway. Whether 53BP1 and NFBD1 are required for activation of kinases and/or for recruitment of substrates at IRIF, however, is not clear. Here we show that both 53BP1 and NFBD1 are required for recruitment of ATR to DNA damage sites, as well as for ATR-dependent phosphorylation in response to DNA damage. NFBD1 is not required for ssDNA generation at DNA damage sites and is not recruited by replication protein A (RPA)-coated ssDNA. We therefore show that recruitment of NFBD1 and/or 53BP1, the factors downstream of H2AX, is independent of ssDNA generation and RPA coating, whereas both ssDNA and RPA coating play key roles in regulation of the ATR-dependent pathway. These novel findings help clarify where NFBD1 functions in DNA damage early responses.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Inactivation of CtIP leads to early embryonic lethality mediated by G1 restraint and to tumorigenesis by haploid insufficiency.

CtIP interacts with a group of tumor suppressor proteins including RB (retinoblastoma protein), BRCA1, Ikaros, and CtBP, which regulate cell cycle progression through transcriptional repression as well as chromatin remodeling. However, how CtIP exerts its biological function in cell cycle progression remains elusive. To address this issue, we generated an inactivated Ctip allele in mice by inserting a neo gene into exon 5. The corresponding Ctip(-/-) embryos died at embryonic day 4.0 (E4.0), and the blastocysts failed to enter S phase but accumulated in G(1), leading to a slightly elevated cell death. Mouse NIH 3T3 cells depleted of Ctip were arrested at G(1) with the concomitant increase in hypophosphorylated Rb and Cdk inhibitors, p21. However, depletion of Ctip failed to arrest Rb(-/-) mouse embryonic fibroblasts (MEF) or human osteosarcoma Saos-2 cells at G(1), suggesting that this arrest is RB dependent. Importantly, the life span of Ctip(+/-) heterozygotes was shortened by the development of multiple types of tumors, predominantly, large lymphomas. The wild-type Ctip allele and protein remained detectable in these tumors, suggesting that haploid insufficiency of Ctip leads to tumorigenesis. Taken together, this finding uncovers a novel G(1)/S regulation in that CtIP counteracts Rb-mediated G(1) restraint. Deregulation of this function leads to a defect in early embryogenesis and contributes, in part, to tumor formation.

Animals↗

PubMed2004

NIMA-related protein kinase 1 is involved early in the ionizing radiation-induced DNA damage response.

Cellular functions of the NimA-related mammalian kinase Nek1 have not been demonstrated to date. Here we show that Nek1 is involved early in the DNA damage response induced by ionizing radiation (IR) and that Nek1 is important for cells to repair and recover from DNA damage. When primary or transformed cells are exposed to IR, Nek1 kinase activity is increased within 4 minutes, and Nek1 expression is up-regulated shortly thereafter and sustained for hours. At the same early time frame after IR that its kinase activity is highest, a portion of Nek1 redistributes in cells from cytoplasm to discrete nuclear foci at sites of DNA double-strand breaks. There it colocalizes with gamma-H2AX and NFBD1/MDC1, two key proteins involved very early in the response to IR-induced DNA double-strand breaks. Finally, Nek1-deficient fibroblasts are much more sensitive to the effects of IR-induced DNA damage than otherwise identical fibroblasts expressing Nek1. These results suggest that Nek1 may function as a kinase early in the DNA damage response pathway.

Animals↗

PubMed2004

Identification of a novel putative non-selenocysteine containing phospholipid hydroperoxide glutathione peroxidase (NPGPx) essential for alleviating oxidative stress generated from polyunsaturated fatty acids in breast cancer cells.

A dramatic reduction in the expression of a novel phospholipid hydroperoxide glutathione peroxidase (PHGPx), which incorporates cysteine instead of selenocysteine in the conserved catalytic motif was observed in a microarray analysis using cDNAs amplified from mRNA of Brca1-null mouse embryonic fibroblasts. This non-selenocysteine PHGPx named NPGPx is a cytoplasmic protein with molecular mass of approximately 22 kDa and has little detectable glutathione peroxidase activity in vitro. Ectopic expression of NPGPx in Brca1-null cells that were sensitive to oxidative stress induced by hydrogen peroxide conferred a similar resistance level to that of the wild-type cells, suggesting the importance of this protein in reducing oxidative stress. Expression of NPGPx was found in many tissues, including developing mammary gland. However, the majority of breast cancer cell lines studied (11 of 12) expressed very low or undetectable levels of NPGPx irrespective of BRCA1 status. Re-expression of NPGPx in breast cancer lines, MCF-7 and HCC1937, which have very little or no endogenous NPGPx, induced resistance to eicosapentaenoic acid (an omega-3 type of polyunsaturated fatty acid)-mediated cell death. Conversely, inhibition of the expression of NPGPx by the specific small interfering RNA in HS578T breast cancer cells that originally express substantial amounts of endogenous NPGPx increased their sensitivity to eicosapentaenoic acid-mediated cell death. Thus, NPGPx plays an essential role in breast cancer cells in alleviating oxidative stress generated from polyunsaturated fatty acid metabolism.

Amino Acid Sequence↗

PubMed2004

Purified human SUV3p exhibits multiple-substrate unwinding activity upon conformational change.

Suv3 of Saccharomyces cerevisiae has been classified as a mitochondrial RNA helicase. However, the helicase domain in both yeast and human SUV3 varies considerably from the typical RNA helicase motifs. To investigate its enzymatic activities, a homogeneously purified preparation of SUV3 is required. Expression of a processed form of human SUV3 carrying an N-terminal deletion of 46 amino acids (SUV3DeltaN46) in a yeast suv3 null mutant, which otherwise fails to grow in a nonfermentable carbon source and forms petite colonies in glucose medium, rescues the null phenotype. Through a five-step chromatographic procedure, an 83 kDa SUV3DeltaN46 protein (SUV3-83) and a partially degraded 70 kDa product (SUV3-70) containing amino acids 68-685 were purified to homogeneity. Single- or double-stranded DNA and RNA stimulated ATPase activity of both proteins. SUV3-70, which retains core catalytic domains, can bind and unwind multiple duplex substrates of RNA and DNA with a 5'-3' directionality over a wide range of pH, while SUV3-83 has helicase activity at only acidic pH. ATP, but not nonhydrolyzable ATP, is essential for the unwinding activity, suggesting the requirement of the energy derived from ATP hydrolysis. Consistent with this notion, suv3 mutants containing alanine (A) or arginine (R) substitutions at the conserved lysine residue in the ATP binding site (K213) lost ATPase activity and also failed to unwind the substrates. Importantly, circular dichroism (CD) spectral analysis showed that SUV3-83, at pH 5.0, adopts a conformation similar to that of SUV3-70, suggesting a conformational change in SUV3-83 is required for its helicase activity. The physiological relevance of the multiple-substrate helicase activity of human SUV3 is discussed.

Adenosine Triphosphatases↗

PubMed2003

Assembly of functional ALT-associated promyelocytic leukemia bodies requires Nijmegen Breakage Syndrome 1.

Immortalized cells maintain telomere length through either a telomerase-dependent process or a telomerase-independent pathway termed alternative lengthening of telomeres (ALT). Homologous recombination is implicated in the ALT pathway in both yeast and human ALT cells. In ALT cells, two types of DNA double-strand break repair and homologous recombination factors, the Rad50/Mre11/NBS1 complex and Rad51/Rad52 along with replication factors (RPA) and telomere binding proteins (TRF1 and TRF2), are associated with the ALT-associated PML body (APB). DNA synthesis in late S-G(2) is associated with APBs, which contain telomeric DNA and, are therefore, potential sites for telomere length maintenance. Here, we show that the breast cancer susceptibility gene product, breast cancer susceptibility gene 1, and the human homologue of yeast Rap1, hRap1, are also associated with APBs specifically during late S-G(2) phase of the cell cycle. We additionally show that the localization of the double-strand break repair factors with APBs is distinct from their association with ionizing radiation-induced nuclear foci. To systematically explore the mechanism involved in the assembly of APBs, we examine the role of Nijmegen breakage syndrome 1 (NBS1) and TRF1 in this process, respectively. We demonstrated that NBS1 plays a key role in the assembly and/or recruitment of Rad50, Mre11, and breast cancer susceptibility gene 1, but not Rad51 or TRF1, to APBs. The NH(2) terminus of NBS1, specifically the BRCA1 COOH-terminal domain, is required for this activity. Although TRF1 interacts with NBS1 directly, it is dispensable for the association of either Rad50/Mre11/NBS1 or Rad51 with APBs. Perturbation of the interactions between NBS1/Mre11 and APBs correlates with reduced BrdUrd incorporation associated with APBs, consistent with decreased DNA synthesis at these sites. Taken together, these results support a model in which NBS1 has a vital role in the assembly of APBs, which function to maintain telomeres in human ALT cells.

Acid Anhydride Hydrolases↗

PubMed2003

NFBD1, like 53BP1, is an early and redundant transducer mediating Chk2 phosphorylation in response to DNA damage.

Signaling pathways in response to DNA double strand breaks involve molecular cascades consisting of sensors, transducers, and effector proteins that activate cell cycle checkpoints and recruit repair machinery proteins. NFBD1 (a nuclear factor with BRCT domains protein 1) contains FHA (forkhead-associated), BRCT (breast cancer susceptibility gene 1 carboxyl terminus) domains, and internal repeats and is an early participant in nuclear foci in response to IR. To elucidate its role in the response pathways, small interfering RNA (siRNA) directed against NFDB1 in human cells demonstrated that its absence is associated with increased radio-sensitivity and delayed G(2)/M transition, but not G(1) to S. NFBD1 associates with nuclear foci within minutes following IR, a property similar to histone H2AX, 53BP1, and Chk2, which are all early participants in the DNA damage signaling cascade. Temporal studies show that H2AX is required for the foci positive for NFBD1, but NFBD1 is not needed for 53BP1- and H2AX-positive foci. NFBD1, together with 53BP1, plays a partially redundant role in regulating phosphorylation of the downstream effector protein, Chk2, since abrogation of both diminishes phosphorylated Chk2 in IR-induced foci. These results place NFBD1 parallel to 53BP1 in regulating Chk2 and downstream of H2AX in the recruitment of repair and signaling proteins to sites of DNA damage.

Adaptor Proteins, Signal Transducing↗

PubMed2002

NFBD1, a novel nuclear protein with signature motifs of FHA and BRCT, and an internal 41-amino acid repeat sequence, is an early participant in DNA damage response.

Efficient repair of DNA double-strand breaks depends on the intact signaling cascade, comprising molecules involved in DNA damage signal pathways and checkpoints. Budding yeast Rad9 (scRad9) is required for activation of scRad53 (mammalian homolog Chk2) and transduction of the signal further downstream in this pathway. In the search for a mammalian homolog, three proteins in the human data base, including BRCA1, 53BP1, and nuclear factor with BRCT domains protein 1 (NFBD1), were found to share significant homology with the BRCT motifs of scRad9. Because BRCA1 and 53BP1 are involved in DNA damage responses, a similar role for NFBD1 was tested. We show that NFBD1 is a 250-kDa nuclear protein containing a forkhead-associated motif at its N terminus, two BRCT motifs at its C terminus, and 13 internal repetitions of a 41-amino acid sequence. Five minutes after gamma-irradiation, NFBD1 formed nuclear foci that colocalized with the phosphorylated form of H2AX and Chk2, two phosphorylation events known to be involved in early DNA damage response. NFBD1 foci are also detected in response to camptothecin, etoposide, and methylmethanesulfonate treatments. Deletion of the forkhead-associated motif or the internal repeats of NFBD1 has no effect on DNA damage-induced NFBD1 foci formation. Conversely, deletion of the BRCT motifs abrogates damage-induced NFBD1 foci. Ectopic expression of the BRCT motifs reduced damage-induced NFBD1 foci and compromised phosphorylated Chk2- and phosphorylated H2AX-containing foci. These results suggest that NFBD1, like BRCA1 and 53BP1, participates in the early response to DNA damage.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Phosphorylation of the mitotic regulator protein Hec1 by Nek2 kinase is essential for faithful chromosome segregation.

Hec1 (highly expressed in cancer) plays essential roles in chromosome segregation by interacting through its coiled-coil domains with several proteins that modulate the G(2)/M phase. Hec1 localizes to kinetochores, and its inactivation either by genetic deletion or antibody neutralization leads to severe and lethal chromosomal segregation errors, indicating that Hec1 plays a critical role in chromosome segregation. The mechanisms by which Hec1 is regulated, however, are not known. Here we show that human Hec1 is a serine phosphoprotein and that it binds specifically to the mitotic regulatory kinase Nek2 during G(2)/M. Nek2 phosphorylates Hec1 on serine residue 165, both in vitro and in vivo. Yeast cells are viable without scNek2/Kin3, a close structural homolog of Nek2 that binds to both human and yeast Hec1. When the same yeasts carry an scNek2/Kin3 (D55G) or Nek2 (E38G) mutation to mimic a similar temperature-sensitive nima mutation in Aspergillus, their growth is arrested at the nonpermissive temperature, because the scNek2/Kin3 (D55G) mutant binds to Hec1 but fails to phosphorylate it. Whereas wild-type human Hec1 rescues lethality resulting from deletion of Hec1 in Saccharomyces cerevesiae, a human Hec1 mutant or yeast Hec1 mutant changing Ser(165) to Ala or yeast Hec1 mutant changing Ser(201) to Ala does not. Mutations changing the same Ser residues to Glu, to mimic the negative charge created by phosphorylation, partially rescue lethality but result in a high incidence of errors in chromosomal segregation. These results suggest that cell cycle-regulated serine phosphorylation of Hec1 by Nek2 is essential for faithful chromosome segregation.

Alanine↗

PubMed2002

Cell lineage-specific effects associated with multiple deficiencies of tumor susceptibility genes in Msh2(-/-)Rb(+/-) mice.

Cooperative effects of genetic alterations are frequently observed during carcinogenesis. Mice carrying germ-line mutations in both Rb and p53 or Msh2 and p53 die earlier of tumors than mice with only one of these genes inactivated. Mice with a single wild-type Rb allele develop a syndrome of multiple neuroendocrine neoplasia, and inactivation of both alleles of Msh2 gene predisposes mice to gastrointestinal cancer, lymphomas and tumors of the skin that exhibit a mismatch repair defect. Here we showed that Msh2(-/-)Rb(+/-) mice developed lymphomas later than Msh2-deficient littermates, and the lymphomas observed in Msh2(-/-)Rb(+/-) mice have increased rates of apoptosis and rarely spread to other organs and tissues. In contrast to lymphomagenesis, courses of neuroendocrine, intestinal, and skin carcinogenesis were not significantly influenced by the Msh2(-/-)Rb(+/-) genetic combination. In these mice, neuroendocrine tumors displayed a loss of the remaining wild-type Rb allele but did not show microsatellite instability. On the other hand, the intestinal and skin tumors exhibited microsatellite instability but kept the remaining wild-type allele of Rb. Taken together, these data not only revealed a novel biological interaction between Rb and Msh2 but also cell lineage specificity effects associated with multiple deficiencies in these tumor susceptibility genes.

Animals↗

PubMed2002

BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure.

Mutations in the BRCA2 (breast cancer susceptibility gene 2) tumor suppressor lead to chromosomal instability due to defects in the repair of double-strand DNA breaks (DSBs) by homologous recombination, but BRCA2's role in this process has been unclear. Here, we present the 3.1 angstrom crystal structure of a approximately 90-kilodalton BRCA2 domain bound to DSS1, which reveals three oligonucleotide-binding (OB) folds and a helix-turn-helix (HTH) motif. We also (i) demonstrate that this BRCA2 domain binds single-stranded DNA, (ii) present its 3.5 angstrom structure bound to oligo(dT)9, (iii) provide data that implicate the HTH motif in dsDNA binding, and (iv) show that BRCA2 stimulates RAD51-mediated recombination in vitro. These findings establish that BRCA2 functions directly in homologous recombination and provide a structural and biochemical basis for understanding the loss of recombination-mediated DSB repair in BRCA2-associated cancers.

Amino Acid Sequence↗

PubMed2002

Deficient nonhomologous end-joining activity in cell-free extracts from Brca1-null fibroblasts.

BRCA1 ensures genomic stability, at least in part, through a functional role in DNA damage repair. BRCA1 interacts with the Rad50/Mre11/Nbs1 complex that occupies a central role in DNA double-strand break repair mediated by homologous recombination and nonhomologous end joining (NHEJ). NHEJ can be catalyzed by mammalian whole cell extract in a reaction dependent upon DNA ligase IV, Xrcc4, Ku70, Ku80, and DNA-PKcs. Here, we show that under identical cell-free reaction conditions, the addition of antibodies specific for BRCA1 and Rad 50 but not Rad51, inhibits end-joining activity. Cell extracts derived from Brca1-deficient mouse embryonic fibroblasts exhibit reduced end-joining activity independent of the endogenous protein amounts of DNA ligase IV, Ku80, and Ku70. The Brca1-dependent NHEJ activity predominates at the lower concentrations of Mg2+ (0.5 mM); elevated Mg2+ or Mn2+ concentrations (10 mM) dramatically increase overall end-joining activity and abrogates the requirement for Brca1, Xrcc4, and Ku70. The addition of partially purified BRCA1, in association with Rad50/Mre11/Nbs1 complex, complements the NHEJ deficiency of Brca1-null fibroblast extracts. These results suggest a role for Brca1 in NHEJ and in the maintenance of genome integrity.

Animals↗

PubMed2002

BRCA1 facilitates microhomology-mediated end joining of DNA double strand breaks.

BRCA1 is critical for the maintenance of genomic stability, in part through its interaction with the Rad50.Mre11.Nbs1 complex, which occupies a central role in DNA double strand break repair mediated by nonhomologous end joining (NHEJ) and homologous recombination. BRCA1 has been shown to be required for homology-directed recombination repair. However, the role of BRCA1 in NHEJ, a critical pathway for the repair of double strand breaks and genome stability in mammalian cells, remains elusive. Here, we established a pair of mouse embryonic fibroblasts (MEFs) derived from 9.5-day-old embryos with genotypes Brca1(+/+):p53(-/-) or Brca1(-/-):p53(-/-). The Brca1(-/-):p53(-/-) MEFs appear to be extremely sensitive to ionizing radiation. The contribution of BRCA1 in NHEJ was evaluated in these cells using three different assay systems. First, transfection of a linearized plasmid in which expression of the reporter gene required precise end joining indicated that Brca1(-/-) MEFs display a moderate deficiency when compared with Brca1(+/+) cells. Second, using a retrovirus infection assay dependent on NHEJ, a 5-10-fold reduction in retroviral integration efficiency was observed in Brca1(-/-) MEFs when compared with the Brca1(+/+) MEFs. Third, Brca1(-/-) MEFs exhibited a 50-100-fold deficiency in microhomology-mediated end-joining activity of a defined chromosomal DNA double strand break introduced by a rare cutting endonuclease I-SceI. These results provide evidence that Brca1 has an essential role in microhomology-mediated end joining and suggest a novel molecular basis for its caretaker role in the maintenance of genome integrity.

Adenoviridae↗

PubMed2002

Deficiency of Retinoblastoma gene in mouse embryonic stem cells leads to genetic instability.

Genetic instability has been recognized as a hallmark of human cancers. Retinoblastoma (Rb) tumor suppressor protein has an essential role in modulating cell cycle progression. However, there is no direct evidence supporting its role in maintaining genetic stability. Here, we developed a sensitive method to examine the level of chromosome instability by using retrovirus carrying both positive and negative selectable markers that integrated randomly into individual chromosomes, and the frequency of loss of this selectable chromosomal marker (LOM) in normal mammalian cells was measured. Our results showed that normal mouse embryonic stem (ES) cells had a very low frequency of LOMs, which was less than 10(-8)/cell/generation. In Rb-/- mouse ES cells, the frequency was increased to approximately 10(-5)/cell/generation, whereas in Rb+/- ES cells, the frequency was approximately 10(-7)/cell/generation. LOMs was mediated mainly through chromosomal mechanisms and not through point mutations. These results, therefore, revealed that Rb, with a haploinsufficiency, plays a critical role in the maintenance of chromosome stability. The mystery of why Rb heterozygous carriers have early-onset tumor formation with high penetrance can be, at least, partially explained by this novel activity.

Animals↗