TY - JOUR
T1 - Histone H2A ubiquitination resulting from Brap loss of function connects multiple aging hallmarks and accelerates neurodegeneration
AU - Guo, Yan
AU - Chomiak, Alison A.
AU - Hong, Ye
AU - Lowe, Clara C.
AU - Kopsidas, Caroline A.
AU - Chan, Wen Ching
AU - Andrade, Jorge
AU - Pan, Hongna
AU - Zhou, Xiaoming
AU - Monuki, Edwin S.
AU - Feng, Yuanyi
N1 - Publisher Copyright:
© 2022
PY - 2022/7/15
Y1 - 2022/7/15
N2 - Aging is an intricate process characterized by multiple hallmarks including stem cell exhaustion, genome instability, epigenome alteration, impaired proteostasis, and cellular senescence. Whereas each of these traits is detrimental at the cellular level, it remains unclear how they are interconnected to cause systemic organ deterioration. Here we show that abrogating Brap, a BRCA1-associated protein essential for neurogenesis, results in persistent DNA double-strand breaks and elevation of histone H2A mono- and poly-ubiquitination (H2Aub). These defects extend to cellular senescence and proteasome-mediated histone H2A proteolysis with alterations in cells’ proteomic and epigenetic states. Brap deletion in the mouse brain causes neuroinflammation, impaired proteostasis, accelerated neurodegeneration, and substantially shortened the lifespan. We further show the elevation of H2Aub also occurs in human brain tissues with Alzheimer's disease. These data together suggest that chromatin aberrations mediated by H2Aub may act as a nexus of multiple aging hallmarks and promote tissue-wide degeneration.
AB - Aging is an intricate process characterized by multiple hallmarks including stem cell exhaustion, genome instability, epigenome alteration, impaired proteostasis, and cellular senescence. Whereas each of these traits is detrimental at the cellular level, it remains unclear how they are interconnected to cause systemic organ deterioration. Here we show that abrogating Brap, a BRCA1-associated protein essential for neurogenesis, results in persistent DNA double-strand breaks and elevation of histone H2A mono- and poly-ubiquitination (H2Aub). These defects extend to cellular senescence and proteasome-mediated histone H2A proteolysis with alterations in cells’ proteomic and epigenetic states. Brap deletion in the mouse brain causes neuroinflammation, impaired proteostasis, accelerated neurodegeneration, and substantially shortened the lifespan. We further show the elevation of H2Aub also occurs in human brain tissues with Alzheimer's disease. These data together suggest that chromatin aberrations mediated by H2Aub may act as a nexus of multiple aging hallmarks and promote tissue-wide degeneration.
KW - Biological sciences
KW - Cell biology
KW - Cellular neuroscience
KW - Functional aspects of cell biology
KW - Neuroscience
UR - http://www.scopus.com/inward/record.url?scp=85132433721&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2022.104519
DO - 10.1016/j.isci.2022.104519
M3 - Article
AN - SCOPUS:85132433721
SN - 2589-0042
VL - 25
JO - iScience
JF - iScience
IS - 7
M1 - 104519
ER -