RECQ1 plays a distinct role in cellular response to oxidative DNA damage

Abstract

RECQ1 is the most abundant RecQ homolog in humans but its functions have remained mostly elusive. Biochemically, RECQ1 displays distinct substrate specificities from WRN and BLM, indicating that these RecQ helicases likely perform non-overlapping functions. Our earlier work demonstrated that RECQ1-deficient cells display spontaneous genomic instability. We have obtained key evidence suggesting a unique role of RECQ1 in repair of oxidative DNA damage. We show that similar to WRN, RECQ1 associates with PARP-1 in nuclear extracts and exhibits direct protein interaction in vitro. Deficiency in WRN or BLM helicases have been shown to result in reduced homologous recombination and hyperactivation of PARP under basal condition. However, RECQ1-deficiency did not lead to PARP activation in undamaged cells and nor did it result in reduction in homologous recombination repair. In stark contrast to what is seen in WRN-deficiency, RECQ1-deficient cells hyperactivate PARP in a specific response to H2O2 treatment. RECQ1-deficient cells are more sensitive to oxidative DNA damage and exposure to oxidative stress results in a rapid and reversible recruitment of RECQ1 to chromatin. Chromatin localization of RECQ1 precedes WRN helicase, which has been shown to function in oxidative DNA damage repair. However, oxidative DNA damage-induced chromatin recruitment of these RecQ helicases is independent of PARP activity. As other RecQ helicases are known to interact with PARP-1, this study provides a paradigm to delineate specialized and redundant functions of RecQ homologs in repair of oxidative DNA damage.

Multitasking Roles for Poly(ADP-ribosyl)ation in Aging and Longevity

“…In accordance with these data, PARylation is required for effective replication fork restart upon treatment of cells with sublethal doses of the replicationstress-inducing topoisomerase 1 inhibitor, camptothecin [161]. Specifically, PARP1 activity regulates the timing of replication fork restart by stabilizing forks in the regressed state and recruiting and controlling the RECQ helicase RECQ1 at the stalled fork, which in turn mediates repair and fork restart [162,163].…”

DNA helicases involved in DNA repair and their roles in cancer

“…Despite the absence of phenotypes in unstressed Recql1- knockout mice, primary embryonic fibroblasts from these mice display chromosomal instability 20 . RECQL1-depleted human cells display increased chromosomal instability 21 and sensitivity to ionizing radiation 21 — which is consistent with involvement in double-strand break (DSB) repair 22 — or agents that induce oxidative damage 23 or replication stress 24 (TABLE 2). RECQL1 is highly expressed in various cancers, and its depletion reduces tumour cell proliferation 5,25–28 .…”

Cellular Deficiency of Werner Syndrome Protein or RECQ1 Promotes Genotoxic Potential of Hydroquinone and Benzo[a]pyrene Exposure

“…A very recent study shows that BaP increases double strand break (DSB) repair 11 . WRN and RECQ1 are each involved in the repair of stalled and broken replication forks 12–13 , although the loss of RECQ1 or WRN contributes differently to the repair of DSB by homologous recombination (HR) 14 .…”