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The mismatch repair pathway maintains genomic stability in human pluripotent stem cells (735.1)
Author(s) -
Lin Bo,
Heinen Christopher
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.735.1
Subject(s) - induced pluripotent stem cell , microbiology and biotechnology , cell cycle checkpoint , embryonic stem cell , dna damage , biology , dna repair , stem cell , cell cycle , genome instability , dna mismatch repair , chek1 , carcinogenesis , g2 m dna damage checkpoint , cancer research , apoptosis , genetics , dna , cancer , gene
The mismatch repair (MMR) pathway repairs polymerase errors to help maintain genome stability and prevent tumorigenesis. In addition to repair, MMR is also involved in the induction of cell cycle arrest and apoptosis in response to certain forms of DNA damage. The role of MMR in preserving genome integrity in human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) has not been previously examined. Accumulation of mutation in pluripotent stem cells (PSCs) would be detrimental to the developing organism so we hypothesize that these cells have a robust MMR pathway. We find that ESCs and iPSCs express high levels of MMR proteins and demonstrate strong mismatch repair activity. PSCs are also hypersensitive to DNA damage, showing a high level of apoptosis after treatment with a DNA alkylating agent that is MMR dependent. However, the specific response observed differs from that seen in HeLa or other cancer or primary cells. In these other cells, a permanent G2/M cell cycle arrest is induced in the second cell cycle after damage, however, PSCs directly undergo apoptosis in the first cell cycle. Interestingly, there is no activation of cell cycle checkpoint kinases CHK1 or CHK2, although phosphorylation of H2AX is increased. This more immediate apoptotic response suggests a separate molecular mechanism by which the MMR pathway can induce a response to DNA damage in PSCs. Grant Funding Source : Supported by NIH CA 115783 and CT Stem Cell 13‐SCB‐UCHC‐06