Biomedical subjects

Julio C Morales

Publications and source records attributed to Julio C Morales.

7 recordsLinked to original sources

PubMed2006

53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis.

p53-binding protein 1 (53BP1) participates in the cellular response to DNA double-stranded breaks where it associates with various DNA repair/cell cycle factors including the H2AX histone variant. Mice deficient for 53BP1 (53BP1(-/-)) are sensitive to ionizing radiation and immunodeficient because of impaired Ig heavy chain class switch recombination. Here we show that, as compared with p53(-/-) mice, 53BP1(-/-)/p53(-/-) animals more rapidly develop tumors, including T cell lymphomas and, at lower frequency, B lineage lymphomas, sarcomas, and teratomas. In addition, T cells from animals deficient for both 53BP1 and p53 (53BP1(-/-)/p53(-/-)) display elevated levels of genomic instability relative to T cells deficient for either 53BP1 or p53 alone. In contrast to p53(-/-) T cell lymphomas, which routinely display aneuploidy but not translocations, 53BP1(-/-)/p53(-/-) thymic lymphomas fall into two distinct cytogenetic categories, with many harboring clonal translocations (40%) and the remainder showing aneuploidy (60%). We propose that 53BP1, in the context of p53 deficiency, suppresses T cell lymphomagenesis through its roles in both cell-cycle checkpoints and double-stranded break repair.

Animals↗

PubMed2006

H2AX prevents DNA breaks from progressing to chromosome breaks and translocations.

Histone H2AX promotes DNA double-strand break (DSB) repair and immunoglobulin heavy chain (IgH) class switch recombination (CSR) in B-lymphocytes. CSR requires activation-induced cytidine deaminase (AID) and involves joining of DSB intermediates by end joining. We find that AID-dependent IgH locus chromosome breaks occur at high frequency in primary H2AX-deficient B cells activated for CSR and that a substantial proportion of these breaks participate in chromosomal translocations. Moreover, activated B cells deficient for ATM, 53BP1, or MDC1, which interact with H2AX during the DSB response, show similarly increased IgH locus breaks and translocations. Thus, our findings implicate a general role for these factors in promoting end joining and thereby preventing DSBs from progressing into chromosomal breaks and translocations. As cellular p53 status does not markedly influence the frequency of such events, our results also have implications for how p53 and the DSB response machinery cooperate to suppress generation of lymphomas with oncogenic translocations.

Animals↗

PubMed2005

53BP1 oligomerization is independent of its methylation by PRMT1.

p53 binding protein 1 (53BP1) participates in the repair of DNA double stranded breaks (DSBs) where it is recruited to or near sites of DNA damage. Although little is known about the biochemical functions of 53BP1, the protein possesses several motifs that are likely important for its role as a DNA damage response element. This includes two BRCA1 C-terminal repeats, tandem Tudor domains, and a variety of phosphorylation sites. Here we show that a glycine-arginine rich (GAR) stretch of 53BP1 lying upstream of the Tudor motifs is methylated. We demonstrate that arginine residues within this region are important for asymmetric methylation by the PRMT1 methyltransferase. We further show that sequences upstream of the Tudor domains that do not include the GAR stretch are sufficient for 53BP1 oligomerization in vivo. Thus, although Tudor domains bind methylated proteins, 53BP1 homo-oligomerization occurs independently of Tudor function. Lastly, we find that deficiencies in 53BP1 generate a "hyper-rec" phenotype. Collectively, these data provide new insight into 53BP1, an important component in maintaining genomic stability.

Amino Acid Sequence↗

PubMed2004

Breaking in a new function for casein kinase 2.

DNA damage response mechanisms help ensure the fidelity of chromosomal transmission, and the failure of such mechanisms might lead to premature aging and cancer. A new report has established that casein kinase 2 (CK2), a protein that functions in diverse cellular processes, controls the activity of the DNA repair protein XRCC1. These results indicate that CK2 is a key participant in the cellular response to DNA damage.

Animals↗

PubMed2004

53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination.

The mammalian protein 53BP1 is activated in many cell types in response to genotoxic stress, including DNA double-strand breaks (DSBs). We now examine potential functions for 53BP1 in the specific genomic alterations that occur in B lymphocytes. Although 53BP1 was dispensable for V(D)J recombination and somatic hypermutation (SHM), the processes by which immunoglobulin (Ig) variable region exons are assembled and mutated, it was required for Igh class-switch recombination (CSR), the recombination and deletion process by which Igh constant region genes are exchanged. When stimulated to undergo CSR, 53BP1-deficient cells exhibited no defect in C(H) germline transcription or AID expression, however these cells had a profound decrease in switch junctions. The current findings, in combination with the known 53BP1 functions and how it is activated, implicate the DNA damage response to DSBs in the joining phase of class-switch recombination.

Animals↗

PubMed2003

Role for the BRCA1 C-terminal repeats (BRCT) protein 53BP1 in maintaining genomic stability.

p53-binding protein-1 (53BP1) is phosphorylated in response to DNA damage and rapidly relocalizes to presumptive sites of DNA damage along with Mre11 and the phosphorylated histone 2A variant, gamma-H2AX. 53BP1 associates with the BRCA1 tumor suppressor, and knock-down experiments with small interfering RNA have revealed a role for the protein in the checkpoint response to DNA damage. By generating mice defective in m53BP1 (m53BP1(tr/tr)), we have created an animal model to further explore its biochemical and genetic roles in vivo. We find that m53BP1(tr/tr) animals are growth-retarded and show various immune deficiencies including a specific reduction in thymus size and T cell count. Consistent with a role in responding to DNA damage, we find that m53BP1(tr/tr) mice are sensitive to ionizing radiation (gamma-IR), and cells from these animals exhibit chromosomal abnormalities consistent with defects in DNA repair. Thus, 53BP1 is a critical element in the DNA damage response and plays an integral role in maintaining genomic stability.

Active Transport, Cell Nucleus↗

PubMed2002

DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1.

Activation of the ataxia telangiectasia mutated (ATM) kinase triggers diverse cellular responses to ionizing radiation (IR), including the initiation of cell cycle checkpoints. Histone H2AX, p53 binding-protein 1 (53BP1) and Chk2 are targets of ATM-mediated phosphorylation, but little is known about their roles in signalling the presence of DNA damage. Here, we show that mice lacking either H2AX or 53BP1, but not Chk2, manifest a G2-M checkpoint defect close to that observed in ATM(-/-) cells after exposure to low, but not high, doses of IR. Moreover, H2AX regulates the ability of 53BP1 to efficiently accumulate into IR-induced foci. We propose that at threshold levels of DNA damage, H2AX-mediated concentration of 53BP1 at double-strand breaks is essential for the amplification of signals that might otherwise be insufficient to prevent entry of damaged cells into mitosis.

Animals↗