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The shrinking arterial genome: role of double strand DNA breaks in age‐related DNA deletion (912.9)
Author(s) -
Morgan Richard,
Ives Stephen,
Cawthon Richard,
Andtbacka Robert,
Noyes Dirk,
Lesniewski Lisa,
Richardson Russell,
Donato Anthony
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.912.9
Subject(s) - genome instability , apoptosis , dna damage , dna fragmentation , fragmentation (computing) , werner syndrome , genome , dna repair , histone , biology , gene , dna , medicine , cancer research , endocrinology , genetics , programmed cell death , helicase , ecology , rna
Age‐related genomic instability and subsequent cellular dysfunction may be important processes underlying arterial aging. To assess the novel role of double strand DNA break (DSB)‐mediated DNA deletion in arterial aging, we compared genomic DSB load (gDSB; phosphorylated ser 139 histone H2A.X localized to ALUs: ChIP), genomic ALU content (gALU; proxy for genome size: qPCR), and tumor suppressor protein p53 (P53)/bcl‐2‐associated X protein (BAX)‐dependent apoptotic signaling (P53 bound to BAX gene promoter: ChIP) in arteries from 104 younger ( < 40y), middle‐aged (41‐60y), and older adults ( > 61y). gDSB was ~120% greater in arteries from older adults compared with younger adults ( P = 0.03). gALU was ~40% lower in arteries from middle‐aged and older adults compared with younger adults (all P < 0.01), which indicates DNA deletion and reduced genome size. Subjects in the highest tertile of gDSB had ~30% lower gALU than those in the lowest tertile ( P = 0.03, r = ‐0.17). There was ~260% greater P53/BAX‐dependent apoptotic signaling in arteries from older adults compared with younger adults (all P = 0.03), which could lead to transient reductions in mean genome size via apoptotic DNA fragmentation. Apoptotic signaling was correlated with gDSB (r = 0.34, P < 0.01), but not gALU (r = 0.17, P = 0.08). These findings demonstrate that age‐related reductions in arterial genome size are linked to greater genomic DSB load. Grant Funding Source : Supported by National Institute of Aging‐AG040297, AG029337, AG033196, AG033755