title: Aag DNA glycosylase promotes alkylation-induced tissue damage mediated by Parp1.
abstract: Alkylating agents comprise a major class of front-line cancer chemotherapeutic compounds, and while these agents effectively kill tumor cells, they also damage healthy tissues. Although base excision repair (BER) is essential in repairing DNA alkylation damage, under certain conditions, initiation of BER can be detrimental. Here we illustrate that the alkyladenine DNA glycosylase (AAG) mediates alkylation-induced tissue damage and whole-animal lethality following exposure to alkylating agents. Aag-dependent tissue damage, as observed in cerebellar granule cells, splenocytes, thymocytes, bone marrow cells, pancreatic β-cells, and retinal photoreceptor cells, was detected in wild-type mice, exacerbated in Aag transgenic mice, and completely suppressed in Aag⁻/⁻ mice. Additional genetic experiments dissected the effects of modulating both BER and Parp1 on alkylation sensitivity in mice and determined that Aag acts upstream of Parp1 in alkylation-induced tissue damage; in fact, cytotoxicity in WT and Aag transgenic mice was abrogated in the absence of Parp1. These results provide in vivo evidence that Aag-initiated BER may play a critical role in determining the side-effects of alkylating agent chemotherapies and that Parp1 plays a crucial role in Aag-mediated tissue damage.
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Calvo
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Moroski-Erkul
authors.forename: Annabelle
authors.initials: A
authors.lastname: Lake
authors.forename: Lindsey W
authors.initials: LW
authors.lastname: Eichinger
authors.forename: Dharini
authors.initials: D
authors.lastname: Shah
authors.forename: Iny
authors.initials: I
authors.lastname: Jhun
authors.forename: Prajit
authors.initials: P
authors.lastname: Limsirichai
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
authors.forename: Lisiane B
authors.initials: LB
authors.lastname: Meira
authors.forename: Leona D
authors.initials: LD
authors.lastname: Samson
mesh_terms: D000478:Alkylation / Q000187:drug effects / Q000235:genetics; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics / Q000293:injuries; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D060168:Thymocytes / Q000166:cytology / Q000187:drug effects
chemical_list: D018906:Antineoplastic Agents, Alkylating; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C021565:3-methyladenine-DNA glycosylase; D045647:DNA Glycosylases