The Devil is in the details for DNA mismatch repair

Hsieh, Peggy; Zhang, Yongliang

doi:10.1073/pnas.1702747114

Cited by 34 publications

(26 citation statements)

References 24 publications

(34 reference statements)

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“…MutSα recognizes base‐base mismatches and short (1–2 nt) IDLs, while MutSβ recognizes longer (>2 nt) IDLs. After mismatch recognition, MutSα (or β) recruits MutLα, a heterodimeric complex formed between MLH1 and PMS2 (Hsieh & Zhang, ). MLH1 and PMS2 harbor conserved ATP‐binding domains located in the N‐termini of the enzymes and their C‐terminal domains are involved in heterodimerization, which is necessary for the stability of PMS2 (Guarne, ; Hinrichsen et al., ).…”

Section: Introductionmentioning

confidence: 99%

Biochemical and structural characterization of two variants of uncertain significance in the PMS2 gene

2019

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Lynch syndrome (LS) is an autosomal dominant inherited disorder that is associated with an increased predisposition to certain cancers caused by loss‐of‐function mutations in one of four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2). The diagnosis of LS is often challenged by the identification of missense mutations where the functional effects are not known. These are termed variants of uncertain significance (VUSs) and account for 20%–30% of noncoding and missense mutations. VUSs cause ambiguity during clinical diagnosis and hinder implementation of appropriate medical management. In the current study, we focus on the functional and biological consequences of two nonsynonymous VUSs in PMS2. These variants, c.620G>A and c.123_131delGTTAGTAGA, result in the alteration of glycine 207 to glutamate (p.Gly207Glu) and the deletion of amino acid residues 42–44 (p.Leu42_Glu44del), respectively. While the PMS2 p.Gly207Glu variant retains in vitro MMR and ATPase activities, PMS2 p.Leu42_Glu44del appears to lack such capabilities. Structural and biophysical characterization using circular dichroism, small‐angle X‐ray scattering, and X‐ray crystallography of the N‐terminal domain of the PMS2 variants indicate that the p.Gly207Glu variant is properly folded similar to the wild‐type enzyme, whereas p.Leu42_Glu44del is disordered and prone to aggregation.

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Section: Introductionmentioning

confidence: 99%

Biochemical and structural characterization of two variants of uncertain significance in the PMS2 gene

2019

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“…The DNA MMR pathway is 1 of 5 major DNA repair pathways in humans and is highly conserved from prokaryotes to eukaryotes. [11][12][13][14][15] Mismatches and slippage errors commonly arise during DNA replication and result in non-Watson Crick base pairs or insertion/deletion loops (IDLs). [11][12][13][14][15] The MMR pathway increases replication fidelity by 100 to 1000-fold and is essential for the maintenance of genomic integrity.…”

Section: Introduction and Role Of Pms2 In Mismatch Repairmentioning

confidence: 99%

“…[11][12][13][14][15] Mismatches and slippage errors commonly arise during DNA replication and result in non-Watson Crick base pairs or insertion/deletion loops (IDLs). [11][12][13][14][15] The MMR pathway increases replication fidelity by 100 to 1000-fold and is essential for the maintenance of genomic integrity. 13,14,16 MMR proceeds as 4 distinct steps: mismatch recognition (by the MutS complexes), recruitment of downstream proteins (MutL complex) to the site of the mismatch, excision of the DNA strand that contains the mismatch, and resynthesis by a replicative DNA polymerase.…”

Section: Introduction and Role Of Pms2 In Mismatch Repairmentioning

confidence: 99%

“…13,14,16 MMR proceeds as 4 distinct steps: mismatch recognition (by the MutS complexes), recruitment of downstream proteins (MutL complex) to the site of the mismatch, excision of the DNA strand that contains the mismatch, and resynthesis by a replicative DNA polymerase. [11][12][13][14][15] In humans, the MutS homolog (MSH) MSH2-MSH6 complex, also referred to as MutSα, initiates the repair of single base mismatches and short 1-2 nt IDLs. [11][12][13][14][15] Mismatch recognition and ATP binding induce a conformational change in MutS that is required for the recruitment of the MutLα complex that initiates repair.…”

Section: Introduction and Role Of Pms2 In Mismatch Repairmentioning

confidence: 99%

“…[11][12][13][14][15] In humans, the MutS homolog (MSH) MSH2-MSH6 complex, also referred to as MutSα, initiates the repair of single base mismatches and short 1-2 nt IDLs. [11][12][13][14][15] Mismatch recognition and ATP binding induce a conformational change in MutS that is required for the recruitment of the MutLα complex that initiates repair. [11][12][13][14][15] MutLα is the predominant MutL heterodimer, which is formed by the MutL homolog 1 (MLH1) and the post-meiotic segregation increased 2 (PMS2) proteins.…”

Section: Introduction and Role Of Pms2 In Mismatch Repairmentioning

confidence: 99%

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The changing landscape of Lynch syndrome due to PMS2 mutations

Blount

Prakash

2018

Clinical Genetics

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DNA repair pathways are essential for cellular survival as our DNA is constantly under assault from both exogenous and endogenous DNA damaging agents. Five major mammalian DNA repair pathways exist within a cell to maintain genomic integrity. Of these, the DNA mismatch repair (MMR) pathway is highly conserved among species and is well documented in bacteria. In humans, the importance of MMR is underscored by the discovery that a single mutation in any 1 of 4 genes within the MMR pathway (MLH1, MSH2, MSH6 and PMS2) results in Lynch syndrome (LS). LS is a autosomal dominant condition that predisposes individuals to a higher incidence of many malignancies including colorectal, endometrial, ovarian, and gastric cancers. In this review, we discuss the role of PMS2 in the MMR pathway, the evolving testing criteria used to identify variants in the PMS2 gene, the LS phenotype as well as the autosomal recessive condition called constitutional mismatch repair deficiency syndrome, and current methods used to elucidate the clinical impact of PMS2 mutations.

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Targeting the DNA damage response in cancer

Federica,

Michela,

Giovanna

2024

MedComm

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DNA damage response (DDR) pathway is the coordinated cellular network dealing with the identification, signaling, and repair of DNA damage. It tightly regulates cell cycle progression and promotes DNA repair to minimize DNA damage to daughter cells. Key proteins involved in DDR are frequently mutated/inactivated in human cancers and promote genomic instability, a recognized hallmark of cancer. Besides being an intrinsic property of tumors, DDR also represents a unique therapeutic opportunity. Indeed, inhibition of DDR is expected to delay repair, causing persistent unrepaired breaks, to interfere with cell cycle progression, and to sensitize cancer cells to several DNA‐damaging agents, such as radiotherapy and chemotherapy. In addition, DDR defects in cancer cells have been shown to render these cells more dependent on the remaining pathways, which could be targeted very specifically (synthetic lethal approach). Research over the past two decades has led to the synthesis and testing of hundreds of small inhibitors against key DDR proteins, some of which have shown antitumor activity in human cancers. In parallel, the search for synthetic lethality interaction is broadening the use of DDR inhibitors. In this review, we discuss the state‐of‐art of ataxia‐telangiectasia mutated, ataxia‐telangiectasia‐and‐Rad3‐related protein, checkpoint kinase 1, Wee1 and Polθ inhibitors, highlighting the results obtained in the ongoing clinical trials both in monotherapy and in combination with chemotherapy and radiotherapy.

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The Devil is in the details for DNA mismatch repair

Cited by 34 publications

References 24 publications

Biochemical and structural characterization of two variants of uncertain significance in the PMS2 gene

Biochemical and structural characterization of two variants of uncertain significance in the PMS2 gene

The changing landscape of Lynch syndrome due to PMS2 mutations

Targeting the DNA damage response in cancer

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