Mismatch Repair and Colon Cancer: Mechanisms and Therapies Explored

Li, Stephen K. H.; Martín, Alberto

doi:10.1016/j.molmed.2016.02.003

Cited by 150 publications

(133 citation statements)

References 117 publications

Supporting

Mentioning

115

Contrasting

Unclassified

Order By: Relevance

“…Simultaneously, exonuclease 1 function is also activated for excision of the mismatched DNA. DNA ligase then rejoins the replacement nucleotide(s) of the excised mismatch [4]. …”

Section: Molecular Tumor Boardmentioning

confidence: 99%

“…MSI is characterized by deficiency in repair of base‐base mismatches and/or IDL, leading to missense or frameshift mutations, as well as by frequent insertion and deletions especially at homopolymer and dinucleotide repeats. MSI is commonly associated with hereditary nonpolyposis CRC and a high DNA mutational burden in associated cancers ranging from 10 to 100 mutations per Mb [4], [5]. …”

Section: Molecular Tumor Boardmentioning

confidence: 99%

“…Polymerase α initiates DNA synthesis, then Pol ɛ and Pol δ take over replication of the leading and lagging strands of eukaryotic DNA, respectively. During replication, DNA polymerase α (Pol α) and Pol ɛ, via their exonuclease function, detect and replace mismatched bases in the leading strand by checking against the methylated parent strand [4], [6], [7]. This proofreading function improves replication fidelity by 100‐fold or so.…”

Section: Molecular Tumor Boardmentioning

confidence: 99%

“…Although mutations in POLE can be corrected by MMR, the substantial mutation burden simply overwhelms the MMR pathway and demonstrates the characteristic multifaceted oncogenic progression [4], [7], [8]. In addition, many POLE ‐deficient tumors harbor additional mutations in MMR genes, possibly further contributing to the excessive mutation rate.…”

Section: Molecular Tumor Boardmentioning

confidence: 99%

See 3 more Smart Citations

DNA Polymerase ε Deficiency Leading to an Ultramutator Phenotype: A Novel Clinically Relevant Entity

Castellucci

Goldstein

et al. 2017

The Oncologist

View full text Add to dashboard Cite

Two cases of metastatic colorectal cancer with a POLE mutation, both of which were ultramutated and microsatellite stable, are presented and discussed from the standpoint of the basic biochemical mechanisms leading to a unique phenotype in POLE deficiency, the challenges faced with interpreting the genomic profiling of tumors in this important subset of patients, and the potential clinical implications.

show abstract

“…Simultaneously, exonuclease 1 function is also activated for excision of the mismatched DNA. DNA ligase then rejoins the replacement nucleotide(s) of the excised mismatch [4]. …”

Section: Molecular Tumor Boardmentioning

confidence: 99%

Section: Molecular Tumor Boardmentioning

confidence: 99%

Section: Molecular Tumor Boardmentioning

confidence: 99%

Section: Molecular Tumor Boardmentioning

confidence: 99%

See 2 more Smart Citations

DNA Polymerase ε Deficiency Leading to an Ultramutator Phenotype: A Novel Clinically Relevant Entity

Castellucci

Goldstein

et al. 2017

The Oncologist

View full text Add to dashboard Cite

show abstract

“…28 Cells have developed a series of repair mechanisms to avoid abnormal growth and the accumulation of mutations. These mechanisms include base excision repair, mismatch repair, nucleotide excision repair, cross-link repair and double strand base repair.…”

Section: Discussionmentioning

confidence: 99%

Chk1 and DNA-PK mediate TPEN-induced DNA damage in a ROS dependent manner in human colon cancer cells

Rahal

Fatfat

Hankache

et al. 2016

Cancer Biology & Therapy

View full text Add to dashboard Cite

Recently, we showed that the metal chelator TPEN targets colon cancer cells through redox cycling of copper. Here, we studied the DNA damage potential of TPEN and deciphered the role of Chk1, ATM and DNA-PK in TPEN-induced toxicity in 3 human colon cancer cell lines, HCT116, SW480 and HT29. We also investigated the role of reactive oxygen species (ROS) in TPEN-induced DNA damage. TPEN reduced cell viability in a dose-and time-dependent manner. Cytotoxicity was associated with significant DNA damage and higher expression of g-H2AX protein and activation of ATM/ATR signaling pathway. Cell death by TPEN was dependent on ROS generation as evidenced by the reversal of cell viability, and DNA damage and the abrogation of g-H2AX levels in the presence of antioxidants. Treatment with antioxidants, however, failed to reverse cytotoxicity at high TPEN concentrations (10mM). TPEN-induced cell death was also dependent on the redox cycling of copper since the copper chelator neocuproine inhibited DNA damage and reduced pChk1, g-H2AX, and ATM protein expression. Cell death by low TPEN concentrations, involved ATM/ATR signaling in all 3 cell lines, since pre-incubation with specific inhibitors of ATM and DNA-PK led to the recovery of cells from TPEN-induced DNA damage. In addition, siRNA silencing of Chk1, DNA-PK and ATM abrogated the expression of g-H2AX and reversed cell death, suggesting that Chk1 and DNA-PK mediate TPEN-induced cytotoxicity in colon cancer cells. This study shows for the first time the involvement of Chk1, DNA-PK and ATM in TPEN-induced DNA damage and confirms our previous findings that ROS generation and the redox cycling of copper in response to TPEN are the main mechanisms by which this compound induces cell death in human colon cancer cells. Inhibition of ATM or DNA-PK did not reverse cytotoxicity at high TPEN concentrations that cause excessive levels of ROS and irreversible cellular damage.Abbreviations: ROS, reactive oxygen species; XIAP, X-linked inhibitor of apoptosis; DNA-PK, DNA-dependent protein kinase; ATM, ataxia telangiectasia mutated; ATR, serine/threonine protein kinase ataxia telangiectasia; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; DCFH, 2 0 ,7 0 -Dichlorofluorescin diacetate; NAC, N-acetyL-cysteine; CAT, catalase; DSB, double strand break; SSB, single strand break; Neo, neocuproine; PI, propidium iodide; DDR, DNA damage response

show abstract

Multifocal Organoid Capturing of Colon Cancer Reveals Pervasive Intratumoral Heterogenous Drug Responses

et al. 2021

View full text Add to dashboard Cite

Intratumor heterogeneity (ITH) stands as one of the main difficulties in the treatment of colorectal cancer (CRC) as it causes the development of resistant clones and leads to heterogeneous drug responses. Here, 12 sets of patient-derived organoids (PDOs) and cell lines (PDCs) isolated from multiple regions of single tumors from 12 patients, capturing ITH by multiregion sampling of individual tumors, are presented. Whole-exome sequencing and RNA sequencing of the 12 sets are performed. The PDOs and PDCs of the 12 sets are also analyzed with a clinically relevant 24-compound library to assess their drug responses. The results reveal unexpectedly widespread subregional heterogeneity among PDOs and PDCs isolated from a single tumor, which is manifested by genetic and transcriptional heterogeneity and strong variance in drug responses, while each PDO still recapitulates the major histologic, genomic, and transcriptomic characteristics of the primary tumor. The data suggest an imminent drawback of single biopsy-originated PDO-based clinical diagnosis in evaluating CRC patient responses. Instead, the results indicate the importance of targeting common somatic driver mutations positioned in the trunk of all tumor subregional clones in parallel with a comprehensive understanding of the molecular ITH of each tumor.

show abstract

Mismatch Repair and Colon Cancer: Mechanisms and Therapies Explored

Cited by 150 publications

References 117 publications

DNA Polymerase ε Deficiency Leading to an Ultramutator Phenotype: A Novel Clinically Relevant Entity

DNA Polymerase ε Deficiency Leading to an Ultramutator Phenotype: A Novel Clinically Relevant Entity

Chk1 and DNA-PK mediate TPEN-induced DNA damage in a ROS dependent manner in human colon cancer cells

Multifocal Organoid Capturing of Colon Cancer Reveals Pervasive Intratumoral Heterogenous Drug Responses

Contact Info

Product

Resources

About