Formation of Senescence-Associated Heterochromatin Foci (SAHF)

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R-HSA-2559584
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Pathway
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Homo sapiens
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The process of DNA damage/telomere stress induced senescence culminates in the formation of senescence associated heterochromatin foci (SAHF). These foci represent facultative heterochromatin that is formed in senescent cells. They contribute to the repression of proliferation promoting genes and play an important role in the permanent cell cycle exit that characterizes senescence (Narita et al. 2003 and 2006). SAHF appear as compacted, punctate DAPI stained foci of DNA. Each chromosome is condensed into a single SAH focus, with telomeric and centromeric chromatin located predominantly at its periphery (Funayama et al. 2006, Zhang et al. 2007).

An evolutionarily conserved protein complex of HIRA, ASF1A, UBN1 and CABIN1 plays a crucial role in the SAHF formation. As cells approach senescence, HIRA, ASF1A, UBN1 and CABIN1 accumulate at the PML bodies (Zhang et al. 2005, Banumathy et al. 2009, Rai et al. 2011). PML bodies are punctate nuclear structures that contain PML protein and numerous other proteins and are proposed to be the sites of assembly of macromolecular regulatory complexes and protein modification (Fogal et al. 2000, Guo et al. 2000, Pearson et al. 2000). Recruitment of HIRA to PML bodies coincides with altered chromatin structure and deposition of macroH2A histone H2A variant onto chromatin. As cells become senescent, HIRA, ASF1A, UBN1 and CABIN1 relocate from PML bodies to SAHF. HIRA accumulation at PML bodies is RB1 and TP53 independent, but may require phosphorylation of HIRA serine S697 by GSK3B (Ye, Zerlanko, Kennedy et al. 2007). SAHF formation itself, however, requires functional RB1 and TP53 pathways (Ye, Zerlanko, Zhang et al. 2007).

SAHF contain H3K9Me mark, characteristic of trancriptionally silent chromatin, and HP1, marcoH2A histone H2A variant and HMGA proteins are also components of SAHF (Narita et al. 2006), besides the HIRA:ASF1A:UBN1:CABIN1 complex. A yet unidentified H3K9Me histone methyltransferase may be recruited to SAHF by UBN1 (Banumathy et al. 2009). One of the functions of the HIRA:ASF1A:UBN1:CABIN1 complex is to deposit histone H3.3. variant to chromatin, which influences gene expression (Zhang et al. 2007, Rai et al. 2011).

Further studies are needed to fully elucidate the mechanism of SAHF formation and mechanism by which SAHF promote cell senescence.

Literature References
PubMed ID Title Journal Year
17158953 Loss of linker histone H1 in cellular senescence

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

J. Cell Biol. 2006
19029251 Human UBN1 is an ortholog of yeast Hpc2p and has an essential role in the HIRA/ASF1a chromatin-remodeling pathway in senescent cells

Andrake, M, Schultz, D, Zhang, R, Somaiah, N, Banumathy, G, Marmorstein, R, Adams, PD, Ceulemans, H, Tang, Y, Hoffmann, J

Mol. Cell. Biol. 2009
10910364 PML regulates p53 acetylation and premature senescence induced by oncogenic Ras

Higashimoto, Y, Pandolfi, PP, Saito, S, Fagioli, M, Pearson, M, Minucci, S, Cioce, M, Sebastiani, C, Pelicci, PG, Appella, E, Carbone, R

Nature 2000
17643369 Downregulation of Wnt signaling is a trigger for formation of facultative heterochromatin and onset of cell senescence in primary human cells

Ye, X, Zhang, R, Banumathy, G, Zerlanko, B, Adams, PD, Kennedy, A

Mol. Cell 2007
15621527 Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA

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

Dev. Cell 2005
12809602 Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence

Lowe, SW, Narita, M, Narita, M, Hannon, GJ, Heard, E, Spector, DL, Hearn, SA, N?nez, S, Lin, AW

Cell 2003
11025664 The function of PML in p53-dependent apoptosis

Zhong, S, Pandolfi, PP, Shih, A, Gu, W, Guo, A, Luo, J, Salomoni, P

Nat. Cell Biol. 2000
17242198 Definition of pRB- and p53-dependent and -independent steps in HIRA/ASF1a-mediated formation of senescence-associated heterochromatin foci

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

Mol. Cell. Biol. 2007
17242207 Molecular dissection of formation of senescence-associated heterochromatin foci

Chen, W, Zhang, R, Adams, PD

Mol. Cell. Biol. 2007
21807893 Human CABIN1 is a functional member of the human HIRA/UBN1/ASF1a histone H3.3 chaperone complex

van Tuyn, J, Rai, TS, McBryan, T, Puri, A, Hoffman, J, Marmorstein, R, Schultz, DC, Adams, PD, Tang, Y, Pchelintsev, NA

Mol. Cell. Biol. 2011
16901784 A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation

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

Cell 2006
11080164 Regulation of p53 activity in nuclear bodies by a specific PML isoform

Sandy, P, Fogal, V, Pandolfi, PP, Sternsdorf, T, Del Sal, G, Will, H, Zacchi, P, Schneider, C, Jensen, K, Gostissa, M

EMBO J. 2000
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