ArticlePLoS genetics2008
Human MLH1 protein participates in genomic damage checkpoint signaling in response to DNA interstrand crosslinks, while MSH2 functions in DNA repair.
Article in PLoS genetics, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 61 citations in OpenAlex.
- microRNA-422a promotes HIV replication and innate immune evasion by targeting MECP2.Molecular therapy. Nucleic acids · 2026Article
- HMGB1 Assists in Overcoming Cisplatin Resistance in Chemoresistant Human Ovarian Cancer Cells.Molecular carcinogenesis · 2026Article
- Genetic Variation ofInternational journal of dentistry · 2026Article
- Aberrant cytoplasmic localization of MLH1 characterizes a cell population that seeds breast cancer recurrence.Nature communications · 2025Article
- Functional Validation of Doxorubicin-Induced Cardiotoxicity-Related Genes.JACC. CardioOncology · 2024Article
- Genome sequencing identifies complex structural MLH1 variant in unsolved Lynch syndrome.Molecular genetics & genomic medicine · 2023Article
- Prime editing optimized RTT permits the correction of the c.8713C>T mutation inMolecular therapy. Nucleic acids · 2022Article
- Article
- The MLH1 ATPase domain is needed for suppressing aberrant formation of interstitial telomeric sequences.DNA repair · 2018Article
- RNF138 confers cisplatin resistance in gastric cancer cells via activating Chk1 signaling pathway.Cancer biology & therapy · 2018Article
- Drugging the Cancers Addicted to DNA Repair.Journal of the National Cancer Institute · 2017Review
- A possible association between mycosis fungoides and Muir-Torre syndrome: Two disorders with microsatellite instability.JAAD case reports · 2017Article
- HuCOP1 contributes to the regulation of DNA repair in keratinocytes.Molecular and cellular biochemistry · 2017Article
- Human MLH1 suppresses the insertion of telomeric sequences at intra-chromosomal sites in telomerase-expressing cells.Nucleic acids research · 2017Article
- Interdependence of DNA mismatch repair proteins MLH1 and MSH2 in apoptosis in human colorectal carcinoma cell lines.Molecular and cellular biochemistry · 2016Article
- Role of mismatch repair proteins in the processing of cisplatin interstrand cross-links.DNA repair · 2015Article
- Crosstalk between BRCA-Fanconi anemia and mismatch repair pathways prevents MSH2-dependent aberrant DNA damage responses.The EMBO journal · 2014Article
- Impact of alternative DNA structures on DNA damage, DNA repair, and genetic instability.DNA repair · 2014Review
- What is wrong with Fanconi anemia cells?Cell cycle (Georgetown, Tex.) · 2014Review
- Epistatic role of base excision repair and mismatch repair pathways in mediating cisplatin cytotoxicity.Nucleic acids research · 2013Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
DNA interstrand crosslinks (ICLs) are among the most toxic types of damage to a cell. For this reason, many ICL-inducing agents are effective therapeutic agents. For example, cisplatin and nitrogen mustards are used for treating cancer and psoralen plus UVA (PUVA) is useful for treating psoriasis. However, repair mechanisms for ICLs in the human genome are not clearly defined. Previously, we have shown that MSH2, the common subunit of the human MutSalpha and MutSbeta mismatch recognition complexes, plays a role in the error-free repair of psoralen ICLs. We hypothesized that MLH1, the common subunit of human MutL complexes, is also involved in the cellular response to psoralen ICLs. Surprisingly, we instead found that MLH1-deficient human cells are more resistant to psoralen ICLs, in contrast to the sensitivity to these lesions displayed by MSH2-deficient cells. Apoptosis was not as efficiently induced by psoralen ICLs in MLH1-deficient cells as in MLH1-proficient cells as determined by caspase-3/7 activity and binding of annexin V. Strikingly, CHK2 phosphorylation was undetectable in MLH1-deficient cells, and phosphorylation of CHK1 was reduced after PUVA treatment, indicating that MLH1 is involved in signaling psoralen ICL-induced checkpoint activation. Psoralen ICLs can result in mutations near the crosslinked sites; however, MLH1 function was not required for the mutagenic repair of these lesions, and so its signaling function appears to have a role in maintaining genomic stability following exposure to ICL-induced DNA damage. Distinguishing the genetic status of MMR-deficient tumors as MSH2-deficient or MLH1-deficient is thus potentially important in predicting the efficacy of treatment with psoralen and perhaps with other ICL-inducing agents.
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