title: Cellular response to alkylating agent MNNG is impaired in STAT1-deficients cells.
abstract: The SN 1 alkylating agents activate the mismatch repair system leading to delayed G2 /M cell cycle arrest and DNA repair with subsequent survival or cell death. STAT1, an anti-proliferative and pro-apoptotic transcription factor is known to potentiate p53 and to affect DNA-damage cellular response. We studied whether STAT1 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 STAT1-proficient or -deficient cell lines, we found that STAT1 is required for: (i) reduction in the extent of DNA lesions, (ii) rapid phosphorylation of T68-CHK2 and of S15-p53, (iii) progression through the G2 /M checkpoint and (iv) long-term survival following treatment with MNNG. Presence of STAT1 is critical for the formation of a p53-DNA complex comprising: STAT1, c-Abl and MLH1 following exposure to MNNG. Importantly, presence of STAT1 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 STAT1 in the signalling pathway activated by the mismatch repair system. This ability of STAT1 to favour resistance to MNNG indicates the targeting of STAT1 pathway as a therapeutic option for enhancing the efficacy of SN1 alkylating agent-based chemotherapy.
authors.affiliation: INSERM, U978, Bobigny, France.|Université Paris 13, UFR SMBH, Sorbonne Paris Cité, Laboratoire d'excellence INFLAMEX, Bobigny, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Ah-Koon
authors.affiliation: INSERM, U978, Bobigny, France.|Université Paris 13, UFR SMBH, Sorbonne Paris Cité, Laboratoire d'excellence INFLAMEX, Bobigny, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Lesage
authors.affiliation: INSERM, U978, Bobigny, France.|Université Paris 13, UFR SMBH, Sorbonne Paris Cité, Laboratoire d'excellence INFLAMEX, Bobigny, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Lemadre
authors.affiliation: INSERM, U978, Bobigny, France.|Université Paris 13, UFR SMBH, Sorbonne Paris Cité, Laboratoire d'excellence INFLAMEX, Bobigny, France.
authors.forename: Inès
authors.initials: I
authors.lastname: Souissi
authors.affiliation: INSERM, U978, Bobigny, France.|Université Paris 13, UFR SMBH, Sorbonne Paris Cité, Laboratoire d'excellence INFLAMEX, Bobigny, France.|AP-HP, GHU-PSSD, Hôpital Avicenne, Service de Biochimie, Bobigny, France.
authors.forename: Remi
authors.initials: R
authors.lastname: Fagard
authors.affiliation: INSERM, U978, Bobigny, France. nadine.varin@inserm.fr.|Université Paris 13, UFR SMBH, Sorbonne Paris Cité, Laboratoire d'excellence INFLAMEX, Bobigny, France. nadine.varin@inserm.fr.
authors.forename: Nadine
authors.initials: N
authors.lastname: Varin-Blank
authors.affiliation: INSERM, U978, Bobigny, France.|Université Paris 13, UFR SMBH, Sorbonne Paris Cité, Laboratoire d'excellence INFLAMEX, Bobigny, France.|AP-HP, GHU-PSSD, Hôpital Avicenne, Service de Biochimie, Bobigny, France.
authors.forename: Emmanuelle E
authors.initials: EE
authors.lastname: Fabre
authors.affiliation: INSERM, U978, Bobigny, France. olivier.schischmanoff@aphp.fr.|Université Paris 13, UFR SMBH, Sorbonne Paris Cité, Laboratoire d'excellence INFLAMEX, Bobigny, France. olivier.schischmanoff@aphp.fr.|AP-HP, GHU-PSSD, Hôpital Avicenne, Service de Biochimie, Bobigny, France. olivier.schischmanoff@aphp.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Schischmanoff
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology*; D020033:Protein Isoforms / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000172:deficiency* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000477:Alkylating Agents; C468783:H2AX protein, human; D006657:Histones; D020033:Protein Isoforms; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D016159:Tumor Suppressor Protein p53; D008769:Methylnitronitrosoguanidine; D000068877:Imatinib Mesylate; D004247:DNA; D064447:Checkpoint Kinase 2; D016315:Proto-Oncogene Proteins c-abl; C578634:CHEK2 protein, human
keywords: MMR; MNNG; STAT1; c-Abl; p53