Open AccessCellular response to alkylating agent MNNG is impaired in STAT 1‐deficients cells
Author(s) -
AhKoon Laurent,
Lesage Denis,
Lemadre Elodie,
Souissi Inès,
Fagard Remi,
VarinBlank Nadine,
Fabre Emmanuelle E.,
Schischmanoff Olivier
Publication year - 2016
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12887
Subject(s) - stat , dna damage , cell cycle checkpoint , dna repair , cell cycle , apoptosis , microbiology and biotechnology , tyrosine kinase , jak stat signaling pathway , cancer research , biology , cell growth , phosphorylation , signal transduction , chemistry , dna , biochemistry , stat3
The S N 1 alkylating agents activate the mismatch repair system leading to delayed G 2 /M cell cycle arrest and DNA repair with subsequent survival or cell death. STAT 1, an anti‐proliferative and pro‐apoptotic transcription factor is known to potentiate p53 and to affect DNA ‐damage cellular response. We studied whether STAT 1 may modulate cell fate following activation of the mismatch repair system upon exposure to the alkylating agent N ‐methyl‐ N ′‐nitro‐ N ‐nitrosoguanidine ( MNNG ). Using STAT 1‐proficient or ‐deficient cell lines, we found that STAT 1 is required for: ( i ) reduction in the extent of DNA lesions, ( ii ) rapid phosphorylation of T68‐ CHK 2 and of S15‐p53, ( iii ) progression through the G 2 /M checkpoint and ( iv ) long‐term survival following treatment with MNNG . Presence of STAT 1 is critical for the formation of a p53‐ DNA complex comprising: STAT 1, c‐Abl and MLH 1 following exposure to MNNG . Importantly, presence of STAT 1 allows recruitment of c‐Abl to p53‐ DNA complex and links c‐Abl tyrosine kinase activity to MNNG ‐toxicity. Thus, our data highlight the important modulatory role of STAT 1 in the signalling pathway activated by the mismatch repair system. This ability of STAT 1 to favour resistance to MNNG indicates the targeting of STAT 1 pathway as a therapeutic option for enhancing the efficacy of SN 1 alkylating agent‐based chemotherapy.