User:ImperialSquash/SIR proteins
SIR2
[edit]SIR2 is an NAD-dependent lysine deacetylase.[1] It was the first-discovered member of the sirtuin protein family and is highly conserved, with homologs found in organisms ranging from humans to bacteria[2] and archaea.[1] It interacts with a variety of protein substrates, but does not exhibit strong affinity for DNA, chromatin, or other silencer-binding factors.[1] Instead, it relies on other SIR proteins to find its appropriate silencing target.[1]
In the SIR protein complex, SIR2 removes acetyl groups from the lysine on histone tails H3 and H4[3], 'priming' the nucleosome for chromatin packaging by the SIR3 component of the complex.[4]
Stabilization of rDNA in budding yeast
[edit]Beyond its canonical role in the SIR complex, SIR2 also plays a role in ribosomal DNA (rDNA) repression.[5] As part of the cell's regulation mechanism, rDNA repeats are excised from the chromosome so they cannot be expressed. SIR2 forms a complex with NET1 (a nuclear protein) and CDC14 (a phosphatase) to form the regulator of nucleolar silencing and telophase (RENT) complex.[5] The RENT complex sequesters excised rDNA in 'extrachromosomal circles,' preventing recombination. Accumulation of these circles has been linked to premature aging.[1] SIRT2, SIR2's human analog, has also been linked to age-related disease.[2]
SIR3
[edit]SIR3 is principally involved in heterochromatin spreading, the silencing activity of the SIR protein complex.[1] When overexpressed, SIR3 leads to spreading beyond the normal nucleation site.[1] SIR3 can continue to operate at very low levels of SIR2 and SIR4, but not without them.[3][4] It preferentially binds to unmodified nucleosomes (no acetylation at H4K16 or methylation at H3K79), and relies on SIR2's deacetylation of H4K16 to enhance silencing.[4] H3K79 methylation by DOT1 methyltransferase inhibits SIR3, resulting in an unsilenced chromatin region.[3][4] SIR3 is recruited to a target sequence by RAP1 or ABF1.[1][3]
SIR4
[edit]
SIR4 is involved in scaffolding in the assembly of silenced chromatin.[1][5] It binds to DNA with high affinity, but low specificity.[5] It is most stable when co-expressed with SIR2, but neither SIR2 nor SIR3 are required for it to operate at the telomeres.[1] Each half of the SIR4 protein has distinct responsibilities in heterochromatin spreading. SIR4's N-terminus is required for telomeric silencing, but not for homothallic mating-type (HM) silencing.[1] Conversely, its C-terminus supports HM but not telomeric repression.[1] The N-terminus is positively charged and can be recruited to the telomeric repression site by SIR1 and YKU80.[1] The C-terminus contains the coiled-coil region, which interacts with SIR3 in the hetero trimeric SIR complex and can also interact with RAP1 and YKU70 for recruitment to the telomeric region of the chromosome.[3] The C-terminus also contains the SIR2-interacting domain (SID), where SIR4 can bind to the extended N-terminus of SIR2.[1] SIR2 can catalyze reactions without being bound to SIR4, but this interaction enhances SIR2's catalytic activity.[1]
Resources
[edit]- ^ a b c d e f g h i j k l m n o Kueng, Stephanie; Oppikofer, Mariano; Gasser, Susan M. (2013-11-23). "SIR Proteins and the Assembly of Silent Chromatin in Budding Yeast". Annual Review of Genetics. 47 (1): 275–306. doi:10.1146/annurev-genet-021313-173730. ISSN 0066-4197.
- ^ a b Wu, Qi-Jun; Zhang, Tie-Ning; Chen, Huan-Huan; Yu, Xue-Fei; Lv, Jia-Le; Liu, Yu-Yang; Liu, Ya-Shu; Zheng, Gang; Zhao, Jun-Qi; Wei, Yi-Fan; Guo, Jing-Yi; Liu, Fang-Hua; Chang, Qing; Zhang, Yi-Xiao; Liu, Cai-Gang (2022-12-29). "The sirtuin family in health and disease". Signal Transduction and Targeted Therapy. 7 (1): 1–74. doi:10.1038/s41392-022-01257-8. ISSN 2059-3635. PMC 9797940. PMID 36581622.
{{cite journal}}: CS1 maint: PMC format (link) - ^ a b c d e Lee, Cheng-Sheng; Haber, James E. (2015-04-02). Gellert, Martin; Craig, Nancy (eds.). "Mating-type Gene Switching in Saccharomyces cerevisiae". Microbiology Spectrum. 3 (2): 3.2.29. doi:10.1128/microbiolspec.MDNA3-0013-2014. ISSN 2165-0497.
- ^ a b c d Norris, Anne; Boeke, Jef D. (2010-01-15). "Silent information regulator 3: the Goldilocks of the silencing complex". Genes & Development. 24 (2): 115–122. doi:10.1101/gad.1865510. ISSN 0890-9369. PMID 20080949.
- ^ a b c d Gartenberg, Marc R; Smith, Jeffrey S (2016-08-01). "The Nuts and Bolts of Transcriptionally Silent Chromatin in Saccharomyces cerevisiae". Genetics. 203 (4): 1563–1599. doi:10.1534/genetics.112.145243. ISSN 1943-2631. PMC 4981263. PMID 27516616.
{{cite journal}}: CS1 maint: PMC format (link) - ^ Hsu, Hao-Chi; Wang, Chia-Lin; Wang, Mingzhu; Yang, Na; Chen, Zhi; Sternglanz, Rolf; Xu, Rui-Ming (2013-01-01). "Structural basis for allosteric stimulation of Sir2 activity by Sir4 binding". Genes & Development. 27 (1): 64–73. doi:10.1101/gad.208140.112. ISSN 0890-9369. PMC 3553284. PMID 23307867.
{{cite journal}}: CS1 maint: PMC format (link)