Mammalian mismatch repair: error-free or error-prone?

Peña-Dı́az, Javier; Jiricny, Josef

doi:10.1016/j.tibs.2012.03.001

Cited by 102 publications

(76 citation statements)

References 69 publications

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“…DNA MMR proteins, MLH1 and MSH6, function in sequential steps to initiate repair of DNA mismatches and the abnormalities of these proteins results in the tumorigenesis in colorectal cancer. The mechanism of DNA MMR in humans can be divided into four main steps: (a) mismatched DNA base pairs are recognized by the heterodimers MSH2/ MSH6 (MutSα) and MSH2/MSH3 (MutSβ), which depend on ATP; (b) among the heterodimers MLH1/ PMS2 (MutLα), MLH1/PMS1 (MutLβ) and MLH1/ MLH3 (MutLγ), primarily MutLα is activated in an ATP-dependent manner and binds to MutSα or MutSβ; (c) MutLα with endonuclease activity causes a nick in the mismatch DNA and the DNA strand containing the incorrect nucleotide is removed by exonuclease EXO1; and (d) the excision gap is resynthesized by the replicative DNA polymerase δ using the remaining DNA strand without the incorrect nucleotide as a template [9,10]. In colorectal cancer with Lynch syndrome, tumor progression is accelerated by the rapid accumulation of mutations in coding repetitive sequences (microsatellite sequence) of target genes with growth-related functions, such as growth factor receptors (TGFBR2 and IGF2R) and genes involved in apoptosis (BAX) and DNA repair (MSH3 and MSH6) [7,19].…”

Section: Discussionmentioning

confidence: 99%

Atypical pituitary adenoma with MEN1 somatic mutation associated with abnormalities of DNA mismatch repair genes; MLH1 germline mutation and MSH6 somatic mutation

et al. 2017

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Section: Discussionmentioning

confidence: 99%

Atypical pituitary adenoma with MEN1 somatic mutation associated with abnormalities of DNA mismatch repair genes; MLH1 germline mutation and MSH6 somatic mutation

et al. 2017

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“…It degrades the error-containing section of the newly synthesized strand and therefore provides the DNA polymerase with another chance to generate an error-free copy of the template sequence. In MMR-deficient tumor cells, mutation rates are 100 to 1,000 fold greater in comparison to normal cells [123][124][125]. …”

Section: A15 Mismatch Repairmentioning

confidence: 99%

“…MutSα encompasses MSH2 in a complex with MSH6, and primarily responsible for the repair of base substitutions and small mismatched loops. MutSβ consists of MSH2 and MSH3, and repairs both small loops as well as large loop mismatches (~10 nucleotide loops) [125][126][127].…”

Section: R1 Formation Of Mutsα Complexmentioning

confidence: 99%

“…It has an important role in a few DNA repair pathways, including MMR, Base Excision Repair (BER) and Nucleotide Excision Repair (NER). In MMR, it forms a complex with protein RFC that facilitates the loading of PCNA onto primed DNA templates [125,127,128].…”

Section: R4 Formation Of Pcna-rfc Complexmentioning

confidence: 99%

“…It has been suggested that when the sliding clamp of MutS and MutL encounters PCNA and RFC, RFC is displaced, which allows exonuclease EXO1 to access the daughter strand DNA [125,127,129].…”

Section: R5 Displacement Of Rfc and Recruitment Of Exo1mentioning

confidence: 99%

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Computational analysis of DNA repair pathways in breast cancer

Liu¹

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The integrity of the human genome is constantly challenged by a variety of endogenous and exogenous factors such as ultraviolet radiation and cigarette smoke. To deal with these threats, five major DNA repair pathways, which are principally defined by the type of lesions they repair, have evolved. Defects in these repair pathways predispose individuals to a wide variety of cancers, and at the same time can be therapeutically exploited to target tumours with defective DNA repair.Dysregulation of these repair pathways are also frequently observed in cancer, presenting both opportunities and challenges for cancer therapy: downregulated repair pathways sensitise tumours to DNA-damaging therapies, while upregulated repair pathways cause resistance to these therapies.The primary aim of this thesis is to obtain a comprehensive and in-depth understanding of the mechanisms and roles of these major DNA repair pathways in the context of breast cancer. This will be beneficial for predicting response to radiation and chemotherapy, and for developing novel targeted therapies in this common type of malignancy.By careful literature search and consulting a domain expert, the research presented in this thesis started with a manual curation of six DNA repair pathways, including the five major repair pathways and the Fanconi anaemia pathway that is closely associated with breast cancer susceptibility. Six comprehensive pathway figures were generated, each for one repair pathway, describing in total 195 genes and 138 reactions with direct relevance to DNA repair. Moreover, to facilitate a deep understanding of the repair mechanisms, a detailed description for each reaction was given, importantly including the literature references used for curating the reaction. This curation work enables a mechanistic understanding of how cells respond to DNA damage, and provides a solid foundation for the subsequent computational analyses.In the second study of this PhD research, I performed a personalised pathway analysis to investigate the status of homologous recombination (HR) pathway dysregulation in individual sporadic breast tumours, its association with HR repair deficiency and its impact on tumour characteristics.Specifically, using the expression values of the HR genes curated in the previous study, I calculated an HR score for each tumour that quantifies the extent of HR pathway dysregulation in that tumour.Based on that score, I observed a great diversity in HR dysregulation between and within gene expression-based breast cancer subtypes. And by comparing to two published HR-defect signatures, I found HR pathway dysregulation reflects HR repair deficiency. Furthermore, I uncovered a novel association between HR pathway dysregulation and chromosomal instability (CIN): tumours with more-dysregulated HR tend to have higher CIN. Although CIN has long been considered to be a iii hallmark of most solid tumours, with recent studies highlighting its importance in tumour evolution and drug resistance, the molecular basis of CIN in spora...

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Mechanisms Underlying Mutational Signatures in Human Cancer

Baez‐Ortega¹

2020

Encyclopedia of Life Sciences

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The somatic mutations in a cancer cell's genome are the outcome of a collection of mutational processes which have operated at various intensities, continuously or intermittently, during the patient's lifetime. Such processes include DNA damage by endogenous and exogenous agents, as well as errors and defects in DNA replication and repair systems. Each mutational process gives rise to one or more distinctive patterns of mutations, known as mutational signatures. These patterns reflect both the mechanisms whereby damage is inflicted on DNA and the repair or replication mechanisms that interact with this damage. Over the last decade, computational analyses of thousands of cancer genomes have led to the construction and refinement of comprehensive catalogues of mutational signatures. By opening a window into the inner biology of individual tumours, mutational signatures have transformed our understanding of carcinogenesis, and have provided the basis for new approaches to clinical assessment and treatment of cancers. Key Concepts The somatic mutations in a cancer genome are the product of a collection of mutational processes which have operated on the organism's cells since the moment of fertilisation. The mechanisms of mutation identified in human cancers include DNA damage by endogenous processes and exogenous mutagens, as well as errors and defects in DNA repair and replication processes. A mutational signature represents a characteristic pattern of mutations that is imprinted on the genome by a particular mutational process. Catalogues of consensus mutational signatures, compiled through the analysis of thousands of cancer genomes, can be exploited to determine the mutational processes that are (or have been) active in a particular tumour. The study of mutational signatures can yield insights into the aetiology of individual tumours, informing about the mechanisms that have actively caused damage to DNA, or prevented the repair of this damage; such mechanisms may include preventable carcinogenic exposures, as well as disruption of potentially targetable cellular processes.

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Mammalian mismatch repair: error-free or error-prone?

Cited by 102 publications

References 69 publications

Atypical pituitary adenoma with <i>MEN1</i> somatic mutation associated with abnormalities of DNA mismatch repair genes; <i>MLH1</i> germline mutation and <i>MSH6</i> somatic mutation

Atypical pituitary adenoma with <i>MEN1</i> somatic mutation associated with abnormalities of DNA mismatch repair genes; <i>MLH1</i> germline mutation and <i>MSH6</i> somatic mutation

Computational analysis of DNA repair pathways in breast cancer

Mechanisms Underlying Mutational Signatures in Human Cancer

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