title: SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism.
abstract: DNA damage elicits a cellular signaling response that initiates cell cycle arrest and DNA repair. Here, we find that DNA damage triggers a critical block in glutamine metabolism, which is required for proper DNA damage responses. This block requires the mitochondrial SIRT4, which is induced by numerous genotoxic agents and represses the metabolism of glutamine into tricarboxylic acid cycle. SIRT4 loss leads to both increased glutamine-dependent proliferation and stress-induced genomic instability, resulting in tumorigenic phenotypes. Moreover, SIRT4 knockout mice spontaneously develop lung tumors. Our data uncover SIRT4 as an important component of the DNA damage response pathway that orchestrates a metabolic block in glutamine metabolism, cell cycle arrest, and tumor suppression.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Seung Min
authors.initials: SM
authors.lastname: Jeong
authors.forename: Cuiying
authors.initials: C
authors.lastname: Xiao
authors.forename: Lydia W S
authors.initials: LW
authors.lastname: Finley
authors.forename: Tyler
authors.initials: T
authors.lastname: Lahusen
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Souza
authors.forename: Kerry
authors.initials: K
authors.lastname: Pierce
authors.forename: Ying-Hua
authors.initials: YH
authors.lastname: Li
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Wang
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Laurent
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: German
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xu
authors.forename: Cuiling
authors.initials: C
authors.lastname: Li
authors.forename: Rui-Hong
authors.initials: RH
authors.lastname: Wang
authors.forename: Jaewon
authors.initials: J
authors.lastname: Lee
authors.forename: Alfredo
authors.initials: A
authors.lastname: Csibi
authors.forename: Richard
authors.initials: R
authors.lastname: Cerione
authors.forename: John
authors.initials: J
authors.lastname: Blenis
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.forename: Alec
authors.initials: A
authors.lastname: Kimmelman
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
authors.forename: Marcia C
authors.initials: MC
authors.lastname: Haigis
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D005973:Glutamine / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D037761:Sirtuins / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D024101:Mitochondrial Proteins; D025521:Tumor Suppressor Proteins; D005973:Glutamine; C514813:SIRT4 protein, mouse; D037761:Sirtuins
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