Dataset Information

Interaction of proliferating cell nuclear antigen with PMS2 is required for MutL? activation and function in mismatch repair.

ABSTRACT: Eukaryotic MutL? (mammalian MLH1-PMS2 heterodimer; MLH1-PMS1 in yeast) functions in early steps of mismatch repair as a latent endonuclease that requires a mismatch, MutS?/?, and DNA-loaded proliferating cell nuclear antigen (PCNA) for activation. We show here that human PCNA and MutL? interact specifically but weakly in solution to form a complex of approximately 1:1 stoichiometry that depends on PCNA interaction with the C-terminal endonuclease domain of the MutL? PMS2 subunit. Amino acid substitution mutations within a PMS2 C-terminal 721QRLIAP motif attenuate or abolish human MutL? interaction with PCNA, as well as PCNA-dependent activation of MutL? endonuclease, PCNA- and DNA-dependent activation of MutL? ATPase, and MutL? function in in vitro mismatch repair. Amino acid substitution mutations within the corresponding yeast PMS1 motif (723QKLIIP) reduce or abolish mismatch repair in vivo. Coupling of a weak allele within this motif (723AKLIIP) with an exo1? null mutation, which individually confer only weak mutator phenotypes, inactivates mismatch repair in the yeast cell.

SUBMITTER: Genschel J

PROVIDER: S-EPMC5441711 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Interaction of proliferating cell nuclear antigen with PMS2 is required for MutLα activation and function in mismatch repair.

Genschel Jochen J Kadyrova Lyudmila Y LY Iyer Ravi R RR Dahal Basanta K BK Kadyrov Farid A FA Modrich Paul P

Proceedings of the National Academy of Sciences of the United States of America 20170424 19

Eukaryotic MutLα (mammalian MLH1-PMS2 heterodimer; MLH1-PMS1 in yeast) functions in early steps of mismatch repair as a latent endonuclease that requires a mismatch, MutSα/β, and DNA-loaded proliferating cell nuclear antigen (PCNA) for activation. We show here that human PCNA and MutLα interact specifically but weakly in solution to form a complex of approximately 1:1 stoichiometry that depends on PCNA interaction with the C-terminal endonuclease domain of the MutLα PMS2 subunit. Amino acid subs ...[more]

PMID: 28439008

Similar Datasets

Project description:BackgroundConstitutional mismatch repair deficiency syndrome results from bi-allelic inheritance of mutations affecting the key DNA mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. Individuals with bi-allelic mutations have a dysfunctional mismatch repair system from birth; as a result, constitutional mismatch repair deficiency syndrome is characterised by early onset malignancies. Fewer than 150 cases have been reported in the literature over the past 20 years. This is the first report of the founder PMS2 mutation - NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11 and its associated cancers in this family.Case presentationThe proband is 30 years old and is alive today. She is of Pakistani ethnic origin and a product of consanguinity. She initially presented aged 24 with painless bleeding per-rectum from colorectal polyps and was referred to clinical genetics. Clinical examination revealed two café-au-lait lesions, lichen planus, and a dermoid cyst. Her sister had been diagnosed in childhood with an aggressive brain tumour followed by colorectal cancer. During follow up, the proband developed 37 colorectal adenomatous polyps, synchronous ovarian and endometrial adenocarcinomas, and ultimately a metachronous gastric adenocarcinoma. DNA sequencing of peripheral lymphocytes revealed a bi-allelic inheritance of the PMS2 mutation NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11. Ovarian tumour tissue demonstrated low microsatellite instability. To date, she has had a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and a total gastrectomy. Aspirin and oestrogen-only hormone replacement therapy provide some chemoprophylaxis and manage postmenopausal symptoms, respectively. An 18-monthly colonoscopy surveillance programme has led to the excision of three high-grade dysplastic colorectal tubular adenomatous polyps. The proband's family pedigree displays multiple relatives with cancers including a likely case of 'true' Turcot syndrome.ConclusionsConstitutional mismatch repair deficiency syndrome should be considered in patients who present with early onset cancer, a strong family history of cancer, and cutaneous features resembling neurofibromatosis type I. Immunohistochemistry analysis of tumour and normal tissue is sensitive and specific for identifying patients with mismatch repair deficiency and should direct DNA sequencing of lymphocytic tissue to establish a diagnosis. Microsatellite instability status appears to be of little value in identifying patients who may have constitutional mismatch repair deficiency syndrome.

Dataset Information

Interaction of proliferating cell nuclear antigen with PMS2 is required for MutL? activation and function in mismatch repair.

Publications

Interaction of proliferating cell nuclear antigen with PMS2 is required for MutLα activation and function in mismatch repair.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets