Replication stress induces specific enrichment of RECQ1 at common fragile sites FRA3B and FRA16D

Lu, Xing; Parvathaneni, Swetha; Hara, Toshifumi; Lal, Ashish; Sharma, Sudha

doi:10.1186/1476-4598-12-29

Cited by 41 publications

(53 citation statements)

References 76 publications

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“…Alternatively, or in addition, regressed fork may be cleaved by structure-specific nucleases to generate a DSB which is subsequently repaired by HR (Figure 4) 23 . Both RECQ1 and WRN are recruited at arrested replication forks 45 . Demonstrated preference of RECQ1, but not WRN, for fork reversal 13 supports increased DSBs in RECQ1-depleted cells exposed to BaP.…”

Section: Discussionmentioning

confidence: 99%

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

Garige

Sharma

2014

Int J Toxicol

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The five known RecQ helicases in humans (RECQ1, BLM, WRN, RECQL4, and RECQ5) have demonstrated roles in diverse genome maintenance mechanisms but their functions in safeguarding the genome from environmental toxicants are poorly understood. Here, we have evaluated a potential role of WRN (mutated in Werner Syndrome) and RECQ1 (the most abundant homolog of WRN) in hydroquinone and benzo[a]pyrene-induced genotoxicity. Silencing of WRN or RECQ1 expression in HeLa cells increased their sensitivity to hydroquinone and benzo[a]pyrene but elicited distinct DNA damage response. RECQ1-depleted cells exhibited increased RPA phosphorylation, Chk1 activation, and DNA double strand breaks as compared to control or WRN-depleted cells following exposure to benzo[a]pyrene treatment. Benzo[a]pyrene-induced double strand breaks in RECQ1-depleted cells were dependent on DNA-PK activity. Notably, loss of WRN in RECQ1-depleted cells ameliorated benzo[a]pyrene toxicity. Collectively, our results provide first indication of non-redundant participation of WRN and RECQ1 in protection from the potentially carcinogenic effects of benzo[a]pyrene and hydroquinone.

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Section: Discussionmentioning

confidence: 99%

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

Garige

Sharma

2014

Int J Toxicol

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“…WRN specifically increases the ability of Pol δ to replicate through common fragile sites, such as FRA16D (207). RECQL1 also localizes to FRA16D and FRA3B in response to replicative stress (208) and may play a similar role in CFS DNA replication.…”

Section: Recq Helicases In Dna Replicationmentioning

confidence: 99%

Human RecQ Helicases in DNA Repair, Recombination, and Replication

Croteau

Popuri

Opresko

et al. 2014

Annu. Rev. Biochem.

481

521

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RecQ helicases are an important family of genome surveillance proteins conserved from bacteria to humans. Each of the five human RecQ helicases plays critical roles in genome maintenance and stability, and the RecQ protein family members are often referred to as guardians of the genome. The importance of these proteins in cellular homeostasis is underscored by the fact that defects in BLM, WRN, and RECQL4 are linked to distinct heritable human disease syndromes. Each human RecQ helicase has a unique set of protein-interacting partners, and these interactions dictate its specialized functions in genome maintenance, including DNA repair, recombination, replication, and transcription. Human RecQ helicases also interact with each other, and these interactions have significant impact on enzyme function. Future research goals in this field include a better understanding of the division of labor among the human RecQ helicases and learning how human RecQ helicases collaborate and cooperate to enhance genome stability.

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“…Cells lacking RECQ1 have a higher rate of spontaneous sister chromatid exchange, are more sensitive to genotoxins, and undergo more double-stranded DNA breaks [8–12]. RECQ1 seems to prevent such DNA breaks by stabilizing stalled or regressed replication forks [13–15]. In addition, RECQ1 is involved in non-homologous end joining [16] and lengthening of telomeres without telomerase [17].…”

Section: Introductionmentioning

confidence: 99%

Site-directed mutants of human RECQ1 reveal functional importance of the zinc binding domain

Sami

Gary

Fang

et al. 2016

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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RecQ helicases are a highly conserved family of ATP-dependent DNA-unwinding enzymes with key roles in DNA replication and repair in all kingdoms of life. The RECQ1 gene encodes the most abundant RecQ homolog in humans. Mutations in RECQ1 significantly increase breast cancer susceptibility. We engineered full-length RECQ1 harboring point mutations in the zinc-binding motif (amino acids 419–480) within the conserved RecQ-specific-C-terminal (RQC) domain known to be critical for diverse biochemical and cellular functions of RecQ helicases. Wild-type RECQ1 contains a zinc ion. Substitution of three of the four conserved cysteine residues that coordinate zinc severely impaired the ATPase and DNA unwinding activities but retained DNA binding and single strand DNA annealing activities. Furthermore, alteration of these residues attenuated zinc binding and significantly changed the overall conformation of full-length RECQ1 protein. In contrast, substitution of cysteine residue at position 471 resulted in a wild-type like RECQ1 protein. Differential contribution of the conserved cysteine residues to the structure and functions of the RECQ1 protein is also inferred by homology modeling. Overall, our results indicate that the zinc binding motif in the RQC domain of RECQ1 is a key structural element that is essential for the structure-functions of RECQ1. Given the recent association of RECQ1 mutations with breast cancer, these observations will contribute to understanding the molecular basis of RECQ1 functions in cancer etiology.

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Replication stress induces specific enrichment of RECQ1 at common fragile sites FRA3B and FRA16D

Cited by 41 publications

References 76 publications

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

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

Human RecQ Helicases in DNA Repair, Recombination, and Replication

Site-directed mutants of human RECQ1 reveal functional importance of the zinc binding domain

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