Diagnosis of Xeroderma pigmentosum variant in a young patient with two novel mutations in the <i>POLH</i> gene

Palma, Armando De; Morren, Marie‐Anne; Ged, Cécile; Pouvelle, Caroline; Taı̈eb, Alain; Aoufouchi, Saïd; Sarasin, Alain

doi:10.1002/ajmg.a.38340

Cited by 8 publications

(5 citation statements)

References 23 publications

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“…35 Inactivating variants of POLH, which encodes the translesion DNA polymerase η are responsible for Xeroderma Pigmentosum, a rare recessive syndrome associated with hypersensitivity to sunlight and a high frequency of skin cancers at an early age. 36,37 Of note, a germline POLH MV (c.2074A>G) was identified by WES in a Lebanese BC-prone family 38 but this variant, predicted to be benign by various tools, was not found in our population. RTEL1 encodes the regulator of telomere elongation helicase 1, which is essential for telomere maintenance and regulation of homologous recombination.…”

Section: Discussionmentioning

confidence: 66%

“…Transcriptome analysis of BC cell lines and tissue identified somatic recurrent rearrangements involving MAST1 and over‐expression of the resulting gene fusion . Inactivating variants of POLH , which encodes the translesion DNA polymerase η are responsible for Xeroderma Pigmentosum, a rare recessive syndrome associated with hypersensitivity to sunlight and a high frequency of skin cancers at an early age . Of note, a germline POLH MV (c.2074A>G) was identified by WES in a Lebanese BC‐prone family but this variant, predicted to be benign by various tools, was not found in our population.…”

Section: Discussionmentioning

confidence: 73%

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Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

Girard

Eon-Marchais

Olaso

et al. 2018

Intl Journal of Cancer

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Pathogenic variants in BRCA1 and BRCA2 only explain the underlying genetic cause of about 10% of hereditary breast and ovarian cancer families. Because of cost‐effectiveness, multigene panel testing is often performed even if the clinical utility of testing most of the genes remains questionable. The purpose of our study was to assess the contribution of rare, deleterious‐predicted variants in DNA repair genes in familial breast cancer (BC) in a well‐characterized and homogeneous population. We analyzed 113 DNA repair genes selected from either an exome sequencing or a candidate gene approach in the GENESIS study, which includes familial BC cases with no BRCA1 or BRCA2 mutation and having a sister with BC ( N = 1,207), and general population controls ( N = 1,199). Sequencing data were filtered for rare loss‐of‐function variants (LoF) and likely deleterious missense variants (MV). We confirmed associations between LoF and MV in PALB2 , ATM and CHEK2 and BC occurrence. We also identified for the first time associations between FANCI , MAST1 , POLH and RTEL1 and BC susceptibility. Unlike other associated genes, carriers of an ATM LoF had a significantly higher risk of developing BC than carriers of an ATM MV (OR LoF = 17.4 vs. OR MV = 1.6; p Het = 0.002). Hence, our approach allowed us to specify BC relative risks associated with deleterious‐predicted variants in PALB2 , ATM and CHEK2 and to add MAST1 , POLH , RTEL1 and FANCI to the list of DNA repair genes possibly involved in BC susceptibility. We also highlight that different types of variants within the same gene can lead to different risk estimates.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 73%

Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

Girard

Eon-Marchais

Olaso

et al. 2018

Intl Journal of Cancer

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“…Previous studies also demonstrated that Polη was particularly efficient at bypassing ultraviolet (UV) radiation-induced cyclobutane pyrimidine dimers, and could accurately insert an A opposite to the T of the dimer (20). Humans that lack Polη suffer from xeroderma pigmentosum variant, resulting in an extreme sensitivity to UV radiation (21). Polη can replicate 8-oxoguanine lesions efficiently and accurately by inserting a C opposite to the damage site (22).…”

Section: Introductionmentioning

confidence: 99%

Lsm12 mediates Pol·q deubiquitination to help Saccharomyces cerevisiae resist oxidative stress

Yao

Shi²,

Chen

et al. 2018

Preprint

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15In Saccharomyces cerevisiae, the Y-family DNA polymerase η (Polη) regulates genome stability 16 in response to different forms of environmental stress by translesion DNA synthesis. To elucidate 17 the role of Polη in oxidative stress-induced DNA damage, we deleted or overexpressed the 18 corresponding gene RAD30, and used transcriptome analysis to screen the potential genes 19 associated with RAD30 to respond to DNA damage. Under 2 mM H 2 O 2 , deletion of RAD30 20 resulted in a 2.2-fold decrease in survival and a 2.8-fold increase in DNA damage, whereas 21 overexpression of RAD30 increased survival and decreased DNA damage by 1.2-and 1.4-fold, 22 IMPORTANCE 34Polη was shown to be critical for cell growth in the yeast Saccharomyces cerevisiae, and deletion 35 of its corresponding gene RAD30 caused a severe growth defect under exposure to oxidative 36 stress with 2 mM H 2 O 2 . Furthermore, we found that Lsm12 physically interacts with Polη and 37 promotes Polη deubiquitination and recruitment. Overall, these findings indicate Lsm12 as a 38 novel regulator mediating Polη deubiquitination that regulates its recruitment in response to 39 DNA damage induced by oxidative stress. 40

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“…Previous studies also demonstrated that Pol was particularly efficient at bypassing UV radiation-induced cyclobutane pyrimidine dimers and could accurately insert an A opposite of the T of the dimer (20). Humans that lack Pol suffer from xeroderma pigmentosum variant, resulting in an extreme sensitivity to UV radiation (21). Pol can replicate 8-oxoguanine lesions efficiently and accurately by inserting a C opposite of the damage site (22).…”

mentioning

confidence: 99%

Lsm12 Mediates Deubiquitination of DNA Polymerase η To Help Saccharomyces cerevisiae Resist Oxidative Stress

Yao

Shi

et al. 2019

Appl Environ Microbiol

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In Saccharomyces cerevisiae, the Y family DNA polymerase (Pol) regulates genome stability in response to different forms of environmental stress by translesion DNA synthesis. To elucidate the role of Pol in oxidative stress-induced DNA damage, we deleted or overexpressed the corresponding gene RAD30 and used transcriptome analysis to screen the potential genes associated with RAD30 to respond to DNA damage. Under 2 mM H 2 O 2 treatment, the deletion of RAD30 resulted in a 2.2-fold decrease in survival and a 2.8-fold increase in DNA damage, whereas overexpression of RAD30 increased survival and decreased DNA damage by 1.2-and 1.4-fold, respectively, compared with the wild-type strain. Transcriptome and phenotypic analyses identified Lsm12 as a main factor involved in oxidative stress-induced DNA damage. Deleting LSM12 caused growth defects, while its overexpression enhanced cell growth under 2 mM H 2 O 2 treatment. This effect was due to the physical interaction of Lsm12 with the UBZ domain of Pol to enhance Pol deubiquitination through Ubp3 and consequently promote Pol recruitment. Overall, these findings demonstrate that Lsm12 is a novel regulator mediating Pol deubiquitination to promote its recruitment under oxidative stress. Furthermore, this study provides a potential strategy to maintain the genome stability of industrial strains during fermentation. IMPORTANCE Pol was shown to be critical for cell growth in the yeast Saccharomyces cerevisiae, and deletion of its corresponding gene RAD30 caused a severe growth defect under exposure to oxidative stress with 2 mM H 2 O 2 . Furthermore, we found that Lsm12 physically interacts with Pol and promotes Pol deubiquitination and recruitment. Overall, these findings indicate Lsm12 is a novel regulator mediating Pol deubiquitination that regulates its recruitment in response to DNA damage induced by oxidative stress.

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Diagnosis of Xeroderma pigmentosum variant in a young patient with two novel mutations in the POLH gene

Cited by 8 publications

References 23 publications

Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

Lsm12 mediates Pol·q deubiquitination to help Saccharomyces cerevisiae resist oxidative stress

Lsm12 Mediates Deubiquitination of DNA Polymerase η To Help Saccharomyces cerevisiae Resist Oxidative Stress

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