SAHF formation

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R-HSA-4647594
Type
Reaction [binding]
Species
Homo sapiens
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Components of the evolutionarily conserved complex of HIRA, ASF1A, UBN1 and CABIN1 accumulate in PML bodies of pre-senescent cells, and relocate to SAHF (senescence-associated heterochromatic foci) in senescent cells, with SAHF relocation depending on the functional RB1 and TP53 pathways (Zhang et al. 2005, Ye et al. 2007, Zhang et al. 2007). The reorganization of heterochromatin into SAHFs is accompanied by reduction in the amount of total and chromatin-bound lamin B1 (LMNB1), and high levels of LMNB1 interfere with SAHF formation (Sadaie et al. 2013). High-mobility group A proteins, HMGA1 and HMGA2, are enriched on chromatin of senescent cells, predominantly localizing to SAHFs, and high HMGA1 and HMGA2 levels, in cooperation with p16-INK4A, promote SAHF formation and repression of E2F target genes in senescent cells. Overexpression of CDK4 and MDM2, which are frequently co-amplified with HMGA2 in cancer cells as a part of 12q13-15 chromosomal band amplification, bypasses HMGA2 and HMGA1 induced cell cycle arrest and SAHF formation (Narita et al. 2006). The accumulation of HMGA proteins on senescent cell chromatin and SAHF formation is accompanied by the loss of the linker histone H1, probably due to a posttranslational mechanism (Funayama et al. 2006). A chromatin remodeling protein EP400 (p400), which is able to bind CDKN1A (p21) promoter and inhibit TP53-mediated activation of CDKN1A transcription, negatively regulates SAHF formation (Chan et al. 2005).

Literature References
PubMed ID Title Journal Year
16901784 A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation

Narita, M, Narita, M, Krizhanovsky, V, Nuñez, S, Chicas, A, Hearn, SA, Myers, MP, Lowe, SW

Cell 2006
15621527 Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA

Zhang, R, Poustovoitov, MV, Ye, X, Santos, HA, Chen, W, Daganzo, SM, Erzberger, JP, Serebriiskii, IG, Canutescu, AA, Dunbrack, RL, Pehrson, JR, Berger, JM, Kaufman, PD, Adams, PD

Dev. Cell 2005
15655109 The p400 E1A-associated protein is a novel component of the p53 --> p21 senescence pathway

Chan, HM, Narita, M, Lowe, SW, Livingston, DM

Genes Dev. 2005
23964094 Redistribution of the Lamin B1 genomic binding profile affects rearrangement of heterochromatic domains and SAHF formation during senescence

Sadaie, M, Salama, R, Carroll, T, Tomimatsu, K, Chandra, T, Young, AR, Narita, M, Pérez-Mancera, PA, Bennett, DC, Chong, H, Kimura, H, Narita, M

Genes Dev. 2013
17242198 Definition of pRB- and p53-dependent and -independent steps in HIRA/ASF1a-mediated formation of senescence-associated heterochromatin foci

Ye, X, Zerlanko, B, Zhang, R, Somaiah, N, Lipinski, M, Salomoni, P, Adams, PD

Mol. Cell. Biol. 2007
17158953 Loss of linker histone H1 in cellular senescence

Funayama, R, Saito, M, Tanobe, H, Ishikawa, F

J. Cell Biol. 2006
17242207 Molecular dissection of formation of senescence-associated heterochromatin foci

Zhang, R, Chen, W, Adams, PD

Mol. Cell. Biol. 2007
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