Histone H2A ubiquitination resulting from Brap loss of function connects multiple aging hallmarks and accelerates neurodegeneration.
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.
Pubmed ID: 35754718 RIS Download
Research resources used in this publication
Additional research tools detected in this publication
None foundAntibodies used in this publication
- Rabbit Anti-Actin Antibody, Unconjugated (RRID:AB_258014)
- Anti Iba1, Rabbit antibody (RRID:AB_839504)
- cyclin A (H-432) (RRID:AB_631329)
- Monoclonal Anti-Vinculin antibody produced in mouse (RRID:AB_477629)
- Mouse Anti-CD68 Monoclonal Antibody, Unconjugated, Clone KP1 (RRID:AB_307338)
- MMP1 antibody (RRID:AB_10724220)
- Anti-Lamin B1 antibody - Nuclear Envelope Marker (RRID:AB_443298)
- Monoclonal Anti-alpha-Tubulin antibody produced in mouse (RRID:AB_477582)
- Monoclonal Anti-GAPDH-Peroxidase antibody produced in mouse (RRID:AB_1078992)
- Nucleoporin p62 (RRID:AB_397863)
- Anti-Ubiquitin K11 linkage Antibody, clone 2A3/2E6 (RRID:AB_2713901)
- Mouse Anti-Ubiquitin, Lys63-Specific Monoclonal antibody, Unconjugated, Clone hwa4c4 (RRID:AB_1587585)
- Rabbit Anti-Ubiquitin, Lys48-Specific Monoclonal antibody, Unconjugated, Clone apu2 (RRID:AB_1587578)
- Anti-Ubiquitin (RRID:AB_2180744)
- Anti-Ubiquitin, clone Ubi-1 (aka 042691GS) (RRID:AB_2180556)
- Cleaved Caspase-3 (Asp175) (5A1E) Rabbit mAb (RRID:AB_2070042)
- Cleaved Caspase-3 (Asp175) Antibody (RRID:AB_2341188)
- Anti-NeuN (RRID:AB_2298772)
- NeuN (D4G4O) XP(R) Rabbit mAb #24307 (RRID:AB_2651140)
- Glial Fibiralliry Acidic Protein (RRID:AB_305808)
- Rat Anti-Mouse CD68 Monoclonal Antibody, Unconjugated, Clone FA-11 (RRID:AB_869007)
- PAI-1 antibody (RRID:AB_2186881)
- MMP2 antibody (RRID:AB_2881746)
- MMP2 antibody (RRID:AB_1950932)
- NEW Anti-RNF168 (RRID:AB_11205761)
- RNF2-human (RRID:AB_10705604)
- Mouse Anti-Lamin A / C Monoclonal Antibody, Unconjugated, Clone 14 (RRID:AB_399533)
- Lamin A/C (4C11) Mouse mAb (RRID:AB_10545756)
- Lamin B (M-20) (RRID:AB_648158)
- Histone H4 antibody (RRID:AB_2886030)
- Rabbit polyclonal anti-histone H4 antibody (RRID:AB_2636967)
- Anti-Histone H3 Antibody, Unconjugated (RRID:AB_331563)
- H3K9me3-human,H3K9me3-mouse (RRID:AB_306848)
- Histone H3 antibody (pAb) (RRID:AB_2793771)
- Histone H2BK120ub1 antibody (mAb) (RRID:AB_2793279)
- Histone H2B antibody (pAb) (RRID:AB_2793163)
- MacroH2A1 Antibody (RRID:AB_2797647)
- Purified anti-H2A.X Phospho (Ser139) (RRID:AB_315794)
- Histone H2A.XS139ph antibody (pAb) (RRID:AB_2793161)
- Phospho-Histone H2A.X (Ser139) Antibody (RRID:AB_2118010)
- Anti-phospho-Histone H2A.X (Ser139) Antibody, clone JBW301 (RRID:AB_309864)
- Anti-Histone H2A.Z Antibody, Unconjugated (RRID:AB_659840)
- Histone H2A.X antibody (RRID:AB_2728764)
- Anti-ubiquityl-Histone H2A, clone E6C5 (RRID:AB_11214408)
- Ubiquityl-Histone H2A (Lys119) (D27C4) XP Rabbit mAb (RRID:AB_10891618)
- Histone H2A antibody (RRID:AB_2885986)
- Histone H2A Antibody II (RRID:AB_2118804)
- Histone H2A, C-terminal antibody (pAb) (RRID:AB_2793270)
- Histone H2A (D6O3A) Antibody (RRID:AB_2687875)
- Histone H1 (AE-4) (RRID:AB_675641)
- Histone H1 antibody (pAb) (RRID:AB_2793314)
- Histone H1.0 antibody (pAb) (RRID:AB_2793627)
- PrP (6D11) (RRID:AB_1128724)
- Tau (TAU-5) (RRID:AB_785931)
- Tau (Tau 46) (RRID:AB_628327)
- KLH-coupled synthetic peptide corresponding to residues surrounding serine 396 of human tau (RRID:AB_1575880)
- Synthetic phospho-peptide (KLH-coupled) corresponding to residues surrounding Thr217 of human Tau (RRID:AB_2622113)
- Phospho-Tau (Ser416) (D7U2P) Rabbit mAb (RRID:AB_2728782)
- Phospho-Tau (Thr231) Polyclonal Antibody (RRID:AB_2533742)
- Phospho-Tau (Ser202, Thr205) Monoclonal Antibody (AT8) (RRID:AB_223647)
- Phospho-Tau (Thr181) Recombinant Rabbit Monoclonal Antibody (5H9L11) (RRID:AB_2532491)
- Fibronectin (RRID:AB_2105706)
- SQSTM1 / P62 antibody [N3C1], Internal (RRID:AB_2038029)
- LC3B Antibody (RRID:AB_915950)
- MAP LC3beta (G-9) (RRID:AB_11150489)
- BRCA1 (C-20) (RRID:AB_630944)
- Anti-ATR, phospho (Ser428) Antibody, Unconjugated (RRID:AB_2290281)
- Phospho-p53 (Ser15) (16G8) Mouse mAb (RRID:AB_331741)
- Phospho-p53 (Ser15) (D4S1H) Rabbit monoclonal Antibody (Rodent Specific) (RRID:AB_2714036)
- p53 (phospho S15) antibody (RRID:AB_301090)
- Phospho-NF-κB p65 (Ser536) (93H1) Rabbit mAb (RRID:AB_331284)
- NF-κB p65 (C22B4) Rabbit monoclonal Antibody (RRID:AB_823578)
- p27 (F-8) (RRID:AB_628074)
- Rabbit Anti-Kip1 (p27) Polyclonal antibody, Unconjugated (RRID:AB_310121)
- Anti-p21waf1, clone HZ52 (RRID:AB_11212534)
Associated grants
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This is a list of tools and resources that we have found mentioned in this publication.
Rabbit Anti-Actin Antibody, Unconjugated (antibody)
RRID:AB_258014
This unknown targets Actin
View all literature mentionsAnti Iba1, Rabbit antibody (antibody)
RRID:AB_839504
This polyclonal targets Iba1
View all literature mentionscyclin A (H-432) (antibody)
RRID:AB_631329
This polyclonal targets CCNA2
View all literature mentionsMonoclonal Anti-Vinculin antibody produced in mouse (antibody)
RRID:AB_477629
This monoclonal targets Vinculin antibody produced in mouse
View all literature mentionsMouse Anti-CD68 Monoclonal Antibody, Unconjugated, Clone KP1 (antibody)
RRID:AB_307338
This monoclonal targets CD68
View all literature mentionsAnti-Lamin B1 antibody - Nuclear Envelope Marker (antibody)
RRID:AB_443298
This polyclonal targets LMNB1
View all literature mentionsMonoclonal Anti-alpha-Tubulin antibody produced in mouse (antibody)
RRID:AB_477582
This monoclonal targets alpha-Tubulin antibody produced in mouse
View all literature mentionsMonoclonal Anti-GAPDH-Peroxidase antibody produced in mouse (antibody)
RRID:AB_1078992
This monoclonal targets GAPDH-Peroxidase antibody produced in mouse
View all literature mentionsNucleoporin p62 (antibody)
RRID:AB_397863
This monoclonal targets Nucleoporin p62
View all literature mentionsAnti-Ubiquitin K11 linkage Antibody, clone 2A3/2E6 (antibody)
RRID:AB_2713901
This monoclonal targets Ubiquitin K11 linkage
View all literature mentionsMouse Anti-Ubiquitin, Lys63-Specific Monoclonal antibody, Unconjugated, Clone hwa4c4 (antibody)
RRID:AB_1587585
This monoclonal targets Ubiquitin, Lys63-Specific
View all literature mentionsRabbit Anti-Ubiquitin, Lys48-Specific Monoclonal antibody, Unconjugated, Clone apu2 (antibody)
RRID:AB_1587578
This monoclonal targets Ubiquitin, Lys48-Specific
View all literature mentionsAnti-Ubiquitin, clone Ubi-1 (aka 042691GS) (antibody)
RRID:AB_2180556
This monoclonal targets Rps27a
View all literature mentionsCleaved Caspase-3 (Asp175) (5A1E) Rabbit mAb (antibody)
RRID:AB_2070042
This monoclonal targets Casp3
View all literature mentionsCleaved Caspase-3 (Asp175) Antibody (antibody)
RRID:AB_2341188
This polyclonal targets Cleaved Caspase-3 (Asp175)
View all literature mentionsNeuN (D4G4O) XP(R) Rabbit mAb #24307 (antibody)
RRID:AB_2651140
This monoclonal targets NeuN
View all literature mentionsGlial Fibiralliry Acidic Protein (antibody)
RRID:AB_305808
This unknown targets The initial immunization was performed with a preparation of full length human recombinant GFAP expressed in bacteria and highly purified
View all literature mentionsRat Anti-Mouse CD68 Monoclonal Antibody, Unconjugated, Clone FA-11 (antibody)
RRID:AB_869007
This monoclonal targets Mouse CD68
View all literature mentionsPAI-1 antibody (antibody)
RRID:AB_2186881
This polyclonal targets PAI-1
View all literature mentionsNEW Anti-RNF168 (antibody)
RRID:AB_11205761
This polyclonal targets NEW RNF168
View all literature mentionsMouse Anti-Lamin A / C Monoclonal Antibody, Unconjugated, Clone 14 (antibody)
RRID:AB_399533
This monoclonal targets Lamin A / C
View all literature mentionsLamin A/C (4C11) Mouse mAb (antibody)
RRID:AB_10545756
This monoclonal targets Lamin A/C
View all literature mentionsHistone H4 antibody (antibody)
RRID:AB_2886030
This polyclonal targets Histone H4
View all literature mentionsRabbit polyclonal anti-histone H4 antibody (antibody)
RRID:AB_2636967
This polyclonal targets Histone H4
View all literature mentionsAnti-Histone H3 Antibody, Unconjugated (antibody)
RRID:AB_331563
This polyclonal targets Histone H3
View all literature mentionsH3K9me3-human,H3K9me3-mouse (antibody)
RRID:AB_306848
This polyclonal targets H3K9me3
View all literature mentionsHistone H3 antibody (pAb) (antibody)
RRID:AB_2793771
This unknown targets Histone H3
View all literature mentionsHistone H2BK120ub1 antibody (mAb) (antibody)
RRID:AB_2793279
This monoclonal targets Histone H2BK120ub1
View all literature mentionsHistone H2B antibody (pAb) (antibody)
RRID:AB_2793163
This unknown targets Histone H2B
View all literature mentionsMacroH2A1 Antibody (antibody)
RRID:AB_2797647
This unknown targets H2AFY
View all literature mentionsPurified anti-H2A.X Phospho (Ser139) (antibody)
RRID:AB_315794
This monoclonal targets H2A.X Phospho Ser139
View all literature mentionsHistone H2A.XS139ph antibody (pAb) (antibody)
RRID:AB_2793161
This unknown targets Histone H2A.XS139ph
View all literature mentionsPhospho-Histone H2A.X (Ser139) Antibody (antibody)
RRID:AB_2118010
This polyclonal targets Phospho-Histone H2A.X (Ser139)
View all literature mentionsAnti-phospho-Histone H2A.X (Ser139) Antibody, clone JBW301 (antibody)
RRID:AB_309864
This monoclonal targets Histone H2A.X pSer139
View all literature mentionsAnti-Histone H2A.Z Antibody, Unconjugated (antibody)
RRID:AB_659840
This unknown targets Histone H2A.Z
View all literature mentionsHistone H2A.X antibody (antibody)
RRID:AB_2728764
This polyclonal targets H2AX
View all literature mentionsAnti-ubiquityl-Histone H2A, clone E6C5 (antibody)
RRID:AB_11214408
This monoclonal targets ubiquityl-Histone H2A clone E6C5
View all literature mentionsUbiquityl-Histone H2A (Lys119) (D27C4) XP Rabbit mAb (antibody)
RRID:AB_10891618
This monoclonal targets Histone H2A (Lys119)
View all literature mentionsHistone H2A antibody (antibody)
RRID:AB_2885986
This polyclonal targets Histone H2A
View all literature mentionsHistone H2A Antibody II (antibody)
RRID:AB_2118804
This polyclonal targets Histone H2A
View all literature mentionsHistone H2A, C-terminal antibody (pAb) (antibody)
RRID:AB_2793270
This unknown targets Histone H2A, C-terminal
View all literature mentionsHistone H2A (D6O3A) Antibody (antibody)
RRID:AB_2687875
This monoclonal targets Histone H2A
View all literature mentionsHistone H1 (AE-4) (antibody)
RRID:AB_675641
This monoclonal targets Histone H1 (AE-4)
View all literature mentionsHistone H1 antibody (pAb) (antibody)
RRID:AB_2793314
This unknown targets Histone H1
View all literature mentionsHistone H1.0 antibody (pAb) (antibody)
RRID:AB_2793627
This unknown targets Histone H1.0
View all literature mentionsPrP (6D11) (antibody)
RRID:AB_1128724
This monoclonal targets PrP (6D11)
View all literature mentionsTau (TAU-5) (antibody)
RRID:AB_785931
This monoclonal targets Tau (TAU-5)
View all literature mentionsKLH-coupled synthetic peptide corresponding to residues surrounding serine 396 of human tau (antibody)
RRID:AB_1575880
This unknown targets Tau pS396
View all literature mentionsSynthetic phospho-peptide (KLH-coupled) corresponding to residues surrounding Thr217 of human Tau (antibody)
RRID:AB_2622113
This unknown targets Tau pT217
View all literature mentionsPhospho-Tau (Ser416) (D7U2P) Rabbit mAb (antibody)
RRID:AB_2728782
This monoclonal targets Phospho-Tau (Ser416)
View all literature mentionsPhospho-Tau (Thr231) Polyclonal Antibody (antibody)
RRID:AB_2533742
This unknown targets Phospho-Tau (Thr231)
View all literature mentionsPhospho-Tau (Ser202, Thr205) Monoclonal Antibody (AT8) (antibody)
RRID:AB_223647
This monoclonal targets Phospho-Tau (Ser202, Thr205)
View all literature mentionsPhospho-Tau (Thr181) Recombinant Rabbit Monoclonal Antibody (5H9L11) (antibody)
RRID:AB_2532491
This recombinant monoclonal targets Phospho-Tau (Thr181)
View all literature mentionsSQSTM1 / P62 antibody [N3C1], Internal (antibody)
RRID:AB_2038029
This polyclonal targets SQSTM1 / P62
View all literature mentionsMAP LC3beta (G-9) (antibody)
RRID:AB_11150489
This monoclonal targets MAP LC3beta (G-9)
View all literature mentionsAnti-ATR, phospho (Ser428) Antibody, Unconjugated (antibody)
RRID:AB_2290281
This polyclonal targets ATR, phospho (Ser428)
View all literature mentionsPhospho-p53 (Ser15) (16G8) Mouse mAb (antibody)
RRID:AB_331741
This monoclonal targets Phospho-p53 (Ser15)
View all literature mentionsPhospho-p53 (Ser15) (D4S1H) Rabbit monoclonal Antibody (Rodent Specific) (antibody)
RRID:AB_2714036
This monoclonal targets Phospho-p53 (Ser15)
View all literature mentionsp53 (phospho S15) antibody (antibody)
RRID:AB_301090
This polyclonal targets p53 (phospho S15)
View all literature mentionsPhospho-NF-κB p65 (Ser536) (93H1) Rabbit mAb (antibody)
RRID:AB_331284
This monoclonal targets NF-KappaB p65, phospho (Ser536)
View all literature mentionsNF-κB p65 (C22B4) Rabbit monoclonal Antibody (antibody)
RRID:AB_823578
This monoclonal targets NF-κB p65
View all literature mentionsp27 (F-8) (antibody)
RRID:AB_628074
This monoclonal targets Epitope corresponds to AA 1-197 representing full length p27 of mouse origin
View all literature mentionsRabbit Anti-Kip1 (p27) Polyclonal antibody, Unconjugated (antibody)
RRID:AB_310121
This polyclonal targets Kip1 (p27)
View all literature mentionsAnti-p21waf1, clone HZ52 (antibody)
RRID:AB_11212534
This monoclonal targets p21waf1 clone HZ52
View all literature mentionsFVB/N-Tg(Thy1-cre)1Vln/J (organism)
RRID:IMSR_JAX:006143
Mus musculus with name FVB/N-Tg(Thy1-cre)1Vln/J from IMSR.
View all literature mentionsB6.129S2-Emx1tm1(cre)Krj/J (organism)
RRID:IMSR_JAX:005628
Mus musculus with name B6.129S2-Emx1tm1(cre)Krj/J from IMSR.
View all literature mentionscyclin A (H-432) (antibody)
RRID:AB_631329
This polyclonal targets CCNA2
View all literature mentions
