ATM activation is impaired in human cells defective in RecQL4 helicase activity

Park, Soon-Young; Kim, Hyunsup; Im, Jun‐Sub; Lee, Joon-Kyu

doi:10.1016/j.bbrc.2018.12.151

Cited by 11 publications

(10 citation statements)

References 23 publications

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“…A recent study showed that RECQL4-depleted U2OS cells were also deficient in ATM dependent checkpoint activation in response to drug induced DNA DSBs. Complementation assays using helicase-inactive point mutants in Walker A (K508G) or Walker B motif (D605A and E606A) further indicated that this was the result of a lack of helicase activity [38]. The ATM pathway plays an equally important role in the physiological processes of DSB repair and recombination, such as V(D)J recombination in T cell development and class switch recombination in B cell activation [39–41].…”

Section: Discussionmentioning

confidence: 99%

ATP-dependent helicase activity is dispensable for the physiological functions of Recql4

et al. 2019

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Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by skin rash (poikiloderma), skeletal dysplasia, small stature, juvenile cataracts, sparse or absent hair, and predisposition to specific malignancies such as osteosarcoma and hematological neoplasms. RTS is caused by germ-line mutations in RECQL4 , a RecQ helicase family member. In vitro studies have identified functions for the ATP-dependent helicase of RECQL4. However, its specific role in vivo remains unclear. To determine the physiological requirement and the biological functions of Recql4 helicase activity, we generated mice with an ATP-binding-deficient knock-in mutation ( Recql4 K525A ). Recql4 K525A/K525A mice were strikingly normal in terms of embryonic development, body weight, hematopoiesis, B and T cell development, and physiological DNA damage repair. However, mice bearing two distinct truncating mutations Recql4 G522Efs and Recql4 R347* , that abolished not only the helicase but also the C-terminal domain, developed a profound bone marrow failure and decrease in survival similar to a Recql4 null allele. These results demonstrate that the ATP-dependent helicase activity of Recql4 is not essential for its physiological functions and that other domains might contribute to this phenotype. Future studies need to be performed to elucidate the complex interactions of RECQL4 domains and its contribution to the development of RTS.

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Section: Discussionmentioning

confidence: 99%

ATP-dependent helicase activity is dispensable for the physiological functions of Recql4

et al. 2019

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“…BLM plays both pro- and anti-recombination roles by stimulating the end resection activity of Dna2 and by the displacement of Rad51 from resected DNA intermediates ( 20 ). RecQL4 has been shown to be recruited very rapidly to DSB sites ( 21 ), and its helicase activity is reportedly required for both HR repair ( 22 , 23 ) and activation of ATM ( 24 ) in response to DNA DSBs. RecQL4 has also been postulated as a participant in 5′-end resection by Mre11 and CtIP during HR repair ( 23 ); however, how the protein plays a role in this process is not known.…”

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confidence: 99%

Stable maintenance of the Mre11-Rad50-Nbs1 complex is sufficient to restore the DNA double-strand break response in cells lacking RecQL4 helicase activity

Kim

Choi

et al. 2021

Journal of Biological Chemistry

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“…In addition to the DRC function of budding yeast Sgs1 mentioned above (21,22), RecQ, the founding member of the RecQ helicase family, initiates the SOS response at perturbed forks by its helicase activity in bacteria (67). The DRC functions have also been described for human RECQ1 (68), RECQ4 (69,70) and WRN (71-73). Although not directly involved in the DRC signaling, BLM is regulated by ATR phosphorylation for cell recovery from S-phase arrest (74).…”

Section: Discussionmentioning

confidence: 99%

The RecQ DNA helicase Rqh1 promotes Rad3^ATRkinase signaling in the DNA replication checkpoint pathway of fission yeast

Ahamad

Khan

2020

Preprint

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Rad3; Cds1; Chk1; ATR; genome integrity. 13Word counts: Abstract: 192 (limit: 200); Main Text: 7048 (limit: 8000). 14 15 16 2 ABSTRACT 17Rad3 is the orthologue of ATR and the sensor kinase of the DNA 18 replication checkpoint in Schizosaccharomyces pombe. Under replication stress, it 19 initiates checkpoint signaling at the forks necessary for maintaining genome 20 stability and cell survival. To better understand the checkpoint initiation process, 21 we have carried out a genetic screen in fission yeast by random mutation of the 22 genome looking for mutants with defects in Rad3 kinase signaling. In addition to 23 the previously reported tel2-C307Y mutant (1), this screen has identified six 24 mutations in rqh1 encoding a RecQ DNA helicase. Surprisingly, these rqh1 25 mutations except a start codon mutation are all in the helicase domain, indicating 26 that the helicase activity of Rqh1 plays an important role in the replication 27 checkpoint. In support of this notion, integration of two helicase-inactive 28 mutations or deletion of rqh1 generated a similar Rad3 signaling defect and 29 heterologous expression of human RECQ1, BLM and RECQ4 restored the Rad3 30 signaling and partially rescued a rqh1 helicase mutant. Therefore, the replication 31 checkpoint function of Rqh1 is highly conserved and mutations in the helicase 32 domain of these human enzymes may cause the checkpoint defect and contribute 33 to the cancer predisposition syndromes. 34 35 INTRODUCTION 36 Multiple cellular mechanisms ensure the accurate transmission of genetic 37 material from one generation to the next. These include proper repair of DNA 38 damage, protection of perturbed DNA replication forks, and the checkpoints that 39 3 coordinate DNA replication and repair with cell cycle progression. Chromosomes 40 are particularly vulnerable to DNA damage during replication as they are 41 decondensed and single-stranded and highly accessible to damaging agents. In 42 addition, other factors such as excessive trinucleotide repeats or insufficient 43supply of dNTPs can also perturb DNA replication. Therefore, DNA replication is 44 subject to exquisite regulations. One such regulation mechanism is the DNA 45 replication checkpoint (DRC). The DRC senses the problems and activates 46 cellular responses such as increased production of dNTPs, cell cycle delay, fork 47 stabilization, and suppression of late firing origins, which work in concert to 48 minimize the mutation rate and ensure accurate and complete duplication of the 49 genome before the cell division. Consistent with its importance in genome 50 stability, the DRC is conserved from yeasts to humans, and defects in the cell 51 signaling pathway cause a wide range of developmental and cancer predisposition 52 syndromes. Although debatable, mutations generated by errors in DNA 53 replication followed by mistakes in repair likely contribute significantly to 54 sporadic cancers [see reviews in references (2-4) ]. 56The current model envisages that a related set of sensor proteins in all 57...

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ATM activation is impaired in human cells defective in RecQL4 helicase activity

Cited by 11 publications

References 23 publications

ATP-dependent helicase activity is dispensable for the physiological functions of Recql4

ATP-dependent helicase activity is dispensable for the physiological functions of Recql4

Stable maintenance of the Mre11-Rad50-Nbs1 complex is sufficient to restore the DNA double-strand break response in cells lacking RecQL4 helicase activity

The RecQ DNA helicase Rqh1 promotes Rad3^ATRkinase signaling in the DNA replication checkpoint pathway of fission yeast

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ATM activation is impaired in human cells defective in RecQL4 helicase activity

Cited by 11 publications

References 23 publications

ATP-dependent helicase activity is dispensable for the physiological functions of Recql4

ATP-dependent helicase activity is dispensable for the physiological functions of Recql4

Stable maintenance of the Mre11-Rad50-Nbs1 complex is sufficient to restore the DNA double-strand break response in cells lacking RecQL4 helicase activity

The RecQ DNA helicase Rqh1 promotes Rad3ATRkinase signaling in the DNA replication checkpoint pathway of fission yeast

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The RecQ DNA helicase Rqh1 promotes Rad3^ATRkinase signaling in the DNA replication checkpoint pathway of fission yeast