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1.
Mol Cell ; 84(3): 447-462.e10, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38244544

RESUMEN

Tumor suppressor BRCA2 functions in homology-directed repair (HDR), the protection of stalled replication forks, and the suppression of replicative gaps, but their relative contributions to genome integrity and chemotherapy response are under scrutiny. Here, we report that mouse and human cells require a RAD51 filament stabilization motif in BRCA2 for fork protection and gap suppression but not HDR. In mice, the loss of fork protection/gap suppression does not compromise genome stability or shorten tumor latency. By contrast, HDR deficiency increases spontaneous and replication stress-induced chromosome aberrations and tumor predisposition. Unlike with HDR, fork protection/gap suppression defects are also observed in Brca2 heterozygous cells, likely due to reduced RAD51 stabilization at stalled forks/gaps. Gaps arise from PRIMPOL activity, which is associated with 5-hydroxymethyl-2'-deoxyuridine sensitivity due to the formation of SMUG1-generated abasic sites and is exacerbated by poly(ADP-ribose) polymerase (PARP) inhibition. However, HDR proficiency has the major role in mitigating sensitivity to chemotherapeutics, including PARP inhibitors.


Asunto(s)
Proteína BRCA2 , Replicación del ADN , Recombinasa Rad51 , Animales , Humanos , Ratones , Proteína BRCA2/metabolismo , Reparación del ADN , Inestabilidad Genómica , Genómica , Recombinasa Rad51/genética , Recombinasa Rad51/metabolismo , Reparación del ADN por Recombinación
2.
bioRxiv ; 2023 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-37090587

RESUMEN

Highlights: Gap suppression requires BRCA2 C-terminal RAD51 binding in mouse and human cells Brca2 heterozygosity in mice results in fork protection and gap suppression defects Gap suppression mitigates sensitivity to hmdU, but only when HDR is unperturbedHDR deficiency is the primary driver of chemotherapeutic sensitivity. eTOC blurb: Lim et al . report that gap suppression as well as fork protection require BRCA2 stabilization of RAD51 filaments in human and mouse cells but have minimal impact on genome integrity, oncogenesis, and drug resistance. BRCA2 suppression of PRIMPOL-mediated replication gaps confers resistance to the nucleotide hmdU, incorporation of which leads to cytotoxic abasic sites.This effect is diminished when HDR is abrogated. Summary: Tumor suppressor BRCA2 functions in homology-directed repair (HDR), protection of stalled replication forks, and suppression of replicative gaps. The relative contributions of these pathways to genome integrity and chemotherapy response are under scrutiny. Here, we report that mouse and human cells require a RAD51 filament stabilization motif in BRCA2 for both fork protection and gap suppression, but not HDR. Loss of fork protection and gap suppression do not compromise genome instability or shorten tumor latency in mice or cause replication stress in human mammary cells. By contrast, HDR deficiency increases spontaneous and replication stress-induced chromosome aberrations and tumor predisposition. Unlike with HDR, fork protection and gap suppression defects are also observed in Brca2 heterozygous mouse cells, likely due to reduced RAD51 stabilization at stalled forks and gaps. Gaps arise from PRIMPOL activity, which is associated with sensitivity to 5-hydroxymethyl-2’-deoxyuridine due to the formation of abasic sites by SMUG1 glycosylase and is exacerbated by poly(ADP-ribose) polymerase inhibition. However, HDR deficiency ultimately modulates sensitivity to chemotherapeutics, including PARP inhibitors.

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