HSF2BP negatively regulates homologous recombination in DNA interstrand crosslink repair

Sato, Koichi; Brandsma, Inger; Rossum-Fikkert, Sari E. van; Verkaik, Nicole S.; Oostra, Anneke B.; Dorsman, Josephine C.; Gent, Dik C. van; Knipscheer, Puck; Kanaar, Roland; Zelensky, Alex N.

doi:10.1093/nar/gkz1219

Cited by 24 publications

(46 citation statements)

References 81 publications

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“…A recent search for new BRCA2 partners identified HSF2BP (also named MEILB2) as another BRCA2-binding protein, endogenously expressed in meiotic cells, and ectopically produced in cancer cells [76,77]. HSF2BP is required for meiotic HR during spermatogenesis; its disruption abolishes the localization of RAD51 and DMC1 recombinases in spermatocytes, leading to errors in DSB repair by meiotic HR and consequently male sterility [78].…”

Section: A Conserved and Disordered Brca2 Region Contains A Cryptic Repeat That Recruits Hsf2bp Thus Triggering Brca2 Degradationmentioning

confidence: 99%

“…Thus, the role of the high affinity interaction between HSF2BP and BRCA2 in meiosis is still unclear. In somatic cells, this interaction interferes with the role of BRCA2 in DNA inter-strand crosslink repair: it triggers proteasome-dependent degradation of BRCA2 [77]. More generally, the high affinity interaction between HSF2BP and BRCA2 might contribute to control the levels of BRCA2 in cells.…”

Section: A Conserved and Disordered Brca2 Region Contains A Cryptic Repeat That Recruits Hsf2bp Thus Triggering Brca2 Degradationmentioning

confidence: 99%

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Intrinsic Disorder and Phosphorylation in BRCA2 Facilitate Tight Regulation of Multiple Conserved Binding Events

et al. 2021

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The maintenance of genome integrity in the cell is an essential process for the accurate transmission of the genetic material. BRCA2 participates in this process at several levels, including DNA repair by homologous recombination, protection of stalled replication forks, and cell division. These activities are regulated and coordinated via cell-cycle dependent modifications. Pathogenic variants in BRCA2 cause genome instability and are associated with breast and/or ovarian cancers. BRCA2 is a very large protein of 3418 amino acids. Most well-characterized variants causing a strong predisposition to cancer are mutated in the C-terminal 700 residues DNA binding domain of BRCA2. The rest of the BRCA2 protein is predicted to be disordered. Interactions involving intrinsically disordered regions (IDRs) remain difficult to identify both using bioinformatics tools and performing experimental assays. However, the lack of well-structured binding sites provides unique functional opportunities for BRCA2 to bind to a large set of partners in a tightly regulated manner. We here summarize the predictive and experimental arguments that support the presence of disorder in BRCA2. We describe how BRCA2 IDRs mediate self-assembly and binding to partners during DNA double-strand break repair, mitosis, and meiosis. We highlight how phosphorylation by DNA repair and cell-cycle kinases regulate these interactions. We finally discuss the impact of cancer-associated variants on the function of BRCA2 IDRs and more generally on genome stability and cancer risk.

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Section: A Conserved and Disordered Brca2 Region Contains A Cryptic Repeat That Recruits Hsf2bp Thus Triggering Brca2 Degradationmentioning

confidence: 99%

Section: A Conserved and Disordered Brca2 Region Contains A Cryptic Repeat That Recruits Hsf2bp Thus Triggering Brca2 Degradationmentioning

confidence: 99%

Intrinsic Disorder and Phosphorylation in BRCA2 Facilitate Tight Regulation of Multiple Conserved Binding Events

et al. 2021

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“…Nascent strands on dsDNA templates were analysed as previously described (Sato et al, 2020). Extracted replication products were digested with HincII, or HincII and ClaI, for 3 hours at 37°C, ethanol-precipitated, and resuspended in 12 μL alkaline loading buffer (50 mM NaOH, 2.5 % Ficoll-400, and 1 mM EDTA).…”

Section: Methodsmentioning

confidence: 99%

Multistep mechanism of DNA replication-coupled G-quadruplex resolution

Sato

Martín-Pintado

Post

et al. 2020

Preprint

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SummaryG-quadruplex (or G4) structures are non-canonical DNA structures that form in guanine-rich sequences and threaten genome stability when not properly resolved. G4 unwinding occurs during S phase via an unknown mechanism. Using Xenopus egg extracts, we define a three-step G4 unwinding mechanism that is coupled to DNA replication. First, the replicative helicase (CMG) stalls at a leading strand G4 structure. Second, the DHX36 helicase mediates the bypass of the CMG past the intact G4 structure, which allows approach of the leading strand to the G4. Third, G4 structure unwinding by the FANCJ helicase enables the DNA polymerase to synthesize past the G4 motif. A G4 on the lagging strand template does not stall CMG, but still requires DNA replication for unwinding. DHX36 and FANCJ have partially redundant roles, conferring robustness to this pathway. Our data reveal a novel genome maintenance pathway that promotes faithful G4 replication thereby avoiding genome instability.

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“…How PALB2, HSF2BP, and BRME1 divide their BRCA2 localizer roles in meiosis among each other, and how these combine with the intrinsic DNA-binding activity of BRCA2, and its ability to autonomously stimulate recombinases in vitro remains to be established. Alternatively, an observed inhibitory effect of HSF2BP on somatic HR caused by its stimulation of proteasomal degradation of BRCA2 ( Sato et al, 2020 ), suggests that HSF2BP (also) affects BRCA2 turnover. The precise functions and regulation of BRCA2 in meiosis may be revealed when better antibodies or other (live) imaging tools for reliable monitoring of BRCA2 abundance and localization in meiocytes become available.…”

Section: Regulation Of Recombinase Assembly At Meiotic Dsbsmentioning

confidence: 99%

High Resolution View on the Regulation of Recombinase Accumulation in Mammalian Meiosis

Mhaskar

Koornneef

Zelensky

et al. 2021

Front. Cell Dev. Biol.

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A distinguishing feature of meiotic DNA double-strand breaks (DSBs), compared to DSBs in somatic cells, is the fact that they are induced in a programmed and specifically orchestrated manner, which includes chromatin remodeling prior to DSB induction. In addition, the meiotic homologous recombination (HR) repair process that follows, is different from HR repair of accidental DSBs in somatic cells. For instance, meiotic HR involves preferred use of the homolog instead of the sister chromatid as a repair template and subsequent formation of crossovers and non-crossovers in a tightly regulated manner. An important outcome of this distinct repair pathway is the pairing of homologous chromosomes. Central to the initial steps in homology recognition during meiotic HR is the cooperation between the strand exchange proteins (recombinases) RAD51 and its meiosis-specific paralog DMC1. Despite our understanding of their enzymatic activity, details on the regulation of their assembly and subsequent molecular organization at meiotic DSBs in mammals have remained largely enigmatic. In this review, we summarize recent mouse data on recombinase regulation via meiosis-specific factors. Also, we reflect on bulk “omics” studies of initial meiotic DSB processing, compare these with studies using super-resolution microscopy in single cells, at single DSB sites, and explore the implications of these findings for our understanding of the molecular mechanisms underlying meiotic HR regulation.

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HSF2BP negatively regulates homologous recombination in DNA interstrand crosslink repair

Cited by 24 publications

References 81 publications

Intrinsic Disorder and Phosphorylation in BRCA2 Facilitate Tight Regulation of Multiple Conserved Binding Events

Intrinsic Disorder and Phosphorylation in BRCA2 Facilitate Tight Regulation of Multiple Conserved Binding Events

Multistep mechanism of DNA replication-coupled G-quadruplex resolution

High Resolution View on the Regulation of Recombinase Accumulation in Mammalian Meiosis

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