Role of Cockayne Syndrome Group B Protein in Replication Stress: Implications for Cancer Therapy

Abstract

A variety of endogenous and exogenous insults are capable of impeding replication fork progression, leading to replication stress. Several SNF2 fork remodelers have been shown to play critical roles in resolving this replication stress, utilizing different pathways dependent upon the nature of the DNA lesion, location on the DNA, and the stage of the cell cycle, to complete DNA replication in a manner preserving genetic integrity. Under certain conditions, however, the attempted repair may lead to additional genetic instability. Cockayne syndrome group B (CSB) protein, a SNF2 chromatin remodeler best known for its role in transcription-coupled nucleotide excision repair, has recently been shown to catalyze fork reversal, a pathway that can provide stability of stalled forks and allow resumption of DNA synthesis without chromosome breakage. Prolonged stalling of replication forks may collapse to give rise to DNA double-strand breaks, which are preferentially repaired by homology-directed recombination. CSB plays a role in repairing collapsed forks by promoting break-induced replication in S phase and early mitosis. In this review, we discuss roles of CSB in regulating the sources of replication stress, replication stress response, as well as the implications of CSB for cancer therapy.

CSB Regulates Pathway Choice in Response to DNA Replication Stress Induced by Camptothecin

“…The toxic combination of CSB and BRCA2 is a feature that has also been previously observed in BRCA2-depleted CSB-KO cells upon exposure to HU, olaparib, and cisplatin [18]. The work presented here lends further support to the previously claimed notion [12,43] that CSB is both a promising biomarker and a potential target in cancer treatment.…”

“…Fork reversal is thought to protect the stability of stalled forks, allowing resumption of DNA synthesis without chromosome breakage [10,11]. Many proteins have been implicated in fork reversal [12,13], including the recombinase RAD51 [14], PARP1 [7,8],…”

CSB and SMARCAL1 compete for RPA32 at stalled forks and differentially control the fate of stalled forks in BRCA2-deficient cells

“…We have shown that loss of CSB restores chemosensitivity in cells depleted with both SMARCAL1 and BRCA2, which is likely due to a defect in CSB-mediated BIR repair of stalled forks ( 17 ). Our finding adds further evidence to growing lines of studies ( 35 , 77 ) suggesting that CSB is a promising target in targeted cancer therapy.…”

“…Like SMARCAL1, CSB (Cockayne syndrome group B) is a DNA translocase that belongs to the SNF2 helicase family ( 12 ). First reported for its role in transcription-coupled nucleotide excision repair (TC-NER) ( 28 , 29 ), CSB has been implicated in DNA DSB repair ( 30–34 ) and the replication stress response ( 17 , 35 , 36 ). CSB possesses an intrinsic fork reversal activity in vitro ( 17 ), which is likely to be highly regulated in vivo .…”

Premature aging in genetic diseases: what conclusions can be drawn for physiological aging

“…CSB protein acts as SNF family chromatin remodeler with ATPase activity that together with CSA protein is best known for the role in transcription-coupled nucleotide-excision DNA repair (TC-NER). These proteins also have a role in repair of DSB, and a variety of other functions as well ( Jaarsma et al, 2013 ; Vessoni et al, 2020 ; Walker and Zhu, 2022 ). Mechanistically, during TC-NER, CSB recognizes nuclear but also mitochondrial DNA lesions ( Scheibye-Knudsen et al, 2012 ; Scheibye-Knudsen et al, 2013 ) that cause RNA stalling in the active transcribed regions, and in turn promotes either backtracking of stalled RNA polymerase or its removal via ubiquitination.…”