BRCA2 functions: from DNA repair to replication fork stabilization

Abstract

Maintaining genomic integrity is essential to preserve normal cellular physiology and to prevent the emergence of several human pathologies including cancer. The breast cancer susceptibility gene 2 (BRCA2, also known as the Fanconi anemia (FA) complementation group D1 (FANCD1)) is a potent tumor suppressor that has been extensively studied in DNA double-stranded break (DSB) repair by homologous recombination (HR). However, BRCA2 participates in numerous other processes central to maintaining genome stability, including DNA replication, telomere homeostasis and cell cycle progression. Consequently, inherited mutations in BRCA2 are associated with an increased risk of breast, ovarian and pancreatic cancers. Furthermore, bi-allelic mutations in BRCA2 are linked to FA, a rare chromosome instability syndrome characterized by aplastic anemia in children as well as susceptibility to leukemia and cancer. Here, we discuss the recent developments underlying the functions of BRCA2 in the maintenance of genomic integrity. The current model places BRCA2 as a central regulator of genome stability by repairing DSBs and limiting replication stress. These findings have direct implications for the development of novel anticancer therapeutic approaches.

FAM35A co-operates with REV7 to coordinate DNA double-strand break repair pathway choice

“…In S/G2 phases of the cell cycle (when sister chromatids are available as templates), HR is activated and can alternatively repair DSBs. One of the key features of HR is the formation of long stretches of single-stranded DNA (ssDNA), a process called DNA end resection (reviewed in (Fradet-Turcotte et al, 2016)). The resulting ssDNA stretches are rapidly coated by RPA, which is subsequently replaced by the recombinase RAD51 to form nucleofilaments that are a prerequisite for the subsequent search of homology, strand invasion and strand exchange before the resolution of the DSB by the HR machinery.…”

SHLD 2/ FAM 35A co‐operates with REV 7 to coordinate DNA double‐strand break repair pathway choice

“…In S/G2 phases of the cell cycle (when sister chromatids are available as templates), HR is activated and can alternatively repair DSBs. One of the key features of HR is the formation of long stretches of single‐stranded DNA (ssDNA), a process called DNA end resection (reviewed in Fradet‐Turcotte et al , ). The resulting ssDNA stretches are rapidly coated by RPA, which is subsequently replaced by the recombinase RAD51 to form nucleofilaments that are a pre‐requisite for the subsequent search of homology, strand invasion, and strand exchange before the resolution of the DSB by the HR machinery.…”

ActiveDriverDB: human disease mutations and genome variation in post-translational modification sites of proteins

“…Consistently, disease-associated SNVs of BRCA2 reported in the ClinVar database are associated with familial breast cancer and hereditary cancer-predisposing syndrome. At the molecular level, BRCA2 is centrally involved in DNA double strand break (DSB) repair by homologous recombination and other aspects of genome stability such as DNA replication, telomere homeostasis and cell cycle progression (50). To safeguard genomic stability at DSBs and stalled replication fork, BRCA2 relies on its ability to interact with RAD51, an interaction that is regulated by cell cycle-dependent kinases (CDKs) (51)(52)(53)(54).…”