DNA helicases FANCM and DDX11 are determinants of PARP inhibitor sensitivity

Stoepker, Chantal; Faramarz, Atiq; Rooimans, Martin A.; Mil, Saskia E. van; Balk, Jesper A.; Velleuer, Eunike; Ameziane, Najim; Riele, Hein te; Winter, Johan P. de

doi:10.1016/j.dnarep.2014.12.003

Cited by 27 publications

(28 citation statements)

References 63 publications

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“…In line with previous reports ( 27 ), we found that DDX11 helicase is required to provide resistance against the PARP inhibitor, olaparib ( SI Appendix , Fig. S3 A ), which causes lesions that are repaired primarily by HR.…”

Section: Resultssupporting

confidence: 92%

Warsaw breakage syndrome DDX11 helicase acts jointly with RAD17 in the repair of bulky lesions and replication through abasic sites

Abe

Ooka

Kawasumi

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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SignificanceWarsaw breakage syndrome, a developmental disorder caused by mutations in the conserved DDX11/ChlR1 DNA helicase, shows features of genome instability partly overlapping with those of Fanconi anemia (FA). Here, using avian cellular models of DDX11 deficiency, we find that DDX11 functions as backup to the FA pathway and facilitates, jointly with the checkpoint clamp 9-1-1, a homologous recombination pathway of DNA bulky-lesion repair that does not affect replication fork speed and stalled fork stability. DDX11 also promotes diversification of the immunoglobulin-variable gene locus by facilitating hypermutation and gene conversion at programmed abasic sites that constitute endogenous replication blocks. The results suggest commonality between postreplicative gap filling and replication through abasic sites and pinpoint DDX11 as a critical player in both these processes.

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Section: Resultssupporting

confidence: 92%

Warsaw breakage syndrome DDX11 helicase acts jointly with RAD17 in the repair of bulky lesions and replication through abasic sites

Abe

Ooka

Kawasumi

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…Overproduction of HSF2BP sensitized cells to PARPi to a similar extent as to ICL agents. Several reports noted increased sensitivity of FA cells to PARPi: a panel of isogenic chicken DT40 cell mutants (Murai et al, 2012), fibroblast from FA mouse models (McCabe et al, 2006), human and mouse head and neck cancer lines (Lombardi et al, 2015), patient lymphoblastoid lines (Stoepker et al, 2015). However, PARPi sensitivity of core FA proteins and I/D2 is much lower than in BRCA2-deficient cells, and lack of sensitivity was concluded for FA-A, -L, -D2, -I, -J patient lines(Kim et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

HSF2BP Negatively Regulates Homologous Recombination in DNA Interstrand Crosslink Repair in Human Cells by Direct Interaction With BRCA2

Brandsma

Sato

Rossum-Fikkert

et al. 2018

Preprint

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1The tumor suppressor BRCA2 is essential for homologous recombination, replication fork 2 stability and DNA interstrand crosslink (ICL) repair in vertebrates. We show that a 3 functionally uncharacterized protein, HSF2BP, is involved in a novel, direct and highly 4 evolutionarily conserved interaction with BRCA2. Although HSF2BP was previously described 5 as testis-specific, we find it is expressed in mouse ES cells, in human cancer cell lines, and in 6 tumor samples. Elevated levels of HSF2BP sensitize human cells to ICL-inducing agents 7 (mitomycin C and cisplatin) and PARP inhibitors, resulting in a phenotype characteristic of 8 cells from Fanconi anemia (FA) patients. We biochemically recapitulate the suppression of 9 ICL repair and establish that excess HSF2BP specifically compromises homologous 10 recombination by preventing BRCA2 and RAD51 loading at the ICL. As increased ectopic 11 expression of HSF2BP occurs naturally, we suggest that it can be considered as a causative 12 agent in FA and a source of cancer-promoting genomic instability. 13 14 2

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“…Interestingly, in addition to BRCA ‐genes, recent studies link several Fanconi anemia pathway genes also with sensitivity to PARP inhibition, including PALB2 , RAD51C, and SLX4, as well as FANCM . Mutations in FANCM were found to cause hypersensitivity to PARP inhibitors, indicating that FANCM actually has a role in the cellular defense against PARP inhibition . This may reflect the several roles FANCM has in cells also outside the Fanconi Anemia pathway, including replisome stability and cell cycle checkpoint activation when DNA repair is needed …”

Section: Discussionmentioning

confidence: 99%

“…35 Mutations in FANCM were found to cause hypersensitivity to PARP inhibitors, indicating that FANCM actually has a role in the cellular defense against PARP inhibition. 37 This may reflect the several roles FANCM has in cells also outside the Fanconi Anemia pathway, including replisome stability and cell cycle checkpoint activation when DNA repair is needed. [38][39][40] Taking the DNA repair functions of FANCM in consideration, we examined nuclear immunohistochemical staining profiles of DNA repair markers of the FANCM c.5101C > T mutation carriers.…”

Section: Cancer Genetics and Epigeneticsmentioning

confidence: 99%

FANCM c.5101C>T mutation associates with breast cancer survival and treatment outcome

Kiiski

Fagerholm

Tervasmäki

et al. 2016

Intl Journal of Cancer

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Breast cancer (BC) is a heterogeneous disease, and different tumor characteristics and genetic variation may affect the clinical outcome. The FANCM c.5101C > T nonsense mutation in the Finnish population associates with increased risk of breast cancer, especially for triple‐negative breast cancer patients. To investigate the association of the mutation with disease prognosis, we studied tumor phenotype, treatment outcome, and patient survival in 3,933 invasive breast cancer patients, including 101 FANCM c.5101C > T mutation carriers and 3,832 non‐carriers. We also examined association of the mutation with nuclear immunohistochemical staining of DNA repair markers in 1,240 breast tumors. The FANCM c.5101C > T mutation associated with poor 10‐year breast cancer‐specific survival (hazard ratio (HR)=1.66, 95% confidence interval (CI) 1.09–2.52, p = 0.018), with a more pronounced survival effect among familial cases (HR = 2.93, 95% CI 1.5–5.76, p = 1.80 × 10−3). Poor disease outcome of the carriers was also found among the estrogen receptor (ER) positive subgroup of patients (HR = 1.8, 95% CI 1.09–2.98, p = 0.021). Reduced survival was seen especially among patients who had not received radiotherapy (HR = 3.43, 95% CI 1.6–7.34, p = 1.50 × 10−3) but not among radiotherapy treated patients (HR = 1.35, 95% CI 0.82–2.23, p = 0.237). Significant interaction was found between the mutation and radiotherapy (p = 0.040). Immunohistochemical analyses show that c.5101C > T carriers have reduced PAR‐activity. Our results suggest that FANCM c.5101C > T nonsense mutation carriers have a reduced breast cancer survival but postoperative radiotherapy may diminish this survival disadvantage.

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DNA helicases FANCM and DDX11 are determinants of PARP inhibitor sensitivity

Cited by 27 publications

References 63 publications

Warsaw breakage syndrome DDX11 helicase acts jointly with RAD17 in the repair of bulky lesions and replication through abasic sites

Warsaw breakage syndrome DDX11 helicase acts jointly with RAD17 in the repair of bulky lesions and replication through abasic sites

HSF2BP Negatively Regulates Homologous Recombination in DNA Interstrand Crosslink Repair in Human Cells by Direct Interaction With BRCA2

FANCM c.5101C>T mutation associates with breast cancer survival and treatment outcome

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