{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n KMT5A, also known as PR‐Set7 or Set8, is the sole enzyme that monomethylates histone H4 at lysine 20 (H4K20me1) and is essential for multiple aspects of chromatin regulation. Its activity establishes a chromatin state critical for proper cell cycle progression by promoting chromatin compaction, ensuring proper mitotic chromosome condensation, and facilitating replication licensing through the efficient assembly of pre‐replication complexes at replication origins."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " During S phase, regulated proteolysis of KMT5A via a PCNA‐ and CRL4(Cdt2)–dependent mechanism ensures that H4K20me1 accumulation remains transient, thereby protecting against replication stress and aberrant chromatin compaction."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}, {"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its role in DNA replication and mitosis, KMT5A exerts important functions in the DNA damage response and cell cycle checkpoint control. It modulates the tumor suppressor p53 by catalyzing specific methylation events that repress or fine‐tune p53‐mediated transcription, thereby influencing the balance between cell cycle arrest and apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In addition, KMT5A’s activity is indispensable during embryonic development; loss of its catalytic function causes early embryonic lethality and severe replication defects."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n The structural basis for substrate recognition and catalytic specificity has been elucidated, revealing how KMT5A selectively deposits the monomethyl mark on H4K20."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Furthermore, KMT5A-dependent H4K20me1 participates in transcriptional regulation during differentiation processes such as adipogenesis and even in the modulation of Wnt signaling, where it activates key transcription factors."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Notably, KMT5A also methylates nonhistone substrates such as PCNA, enhancing its stability and promoting interactions with essential replication factors like FEN1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, KMT5A is a central regulator of chromatin dynamics that integrates signals from DNA replication, repair, and transcription to maintain genomic stability. Its tightly controlled activity throughout the cell cycle ensures proper chromosome condensation and cell cycle progression, while its dysregulation is linked to developmental defects and tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "14"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Mathieu Tardat, Julien Brustel, Olivier Kirsh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The histone H4 Lys 20 methyltransferase PR-Set7 regulates replication origins in mammalian cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Cell Biol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncb2113"}], "href": "https://doi.org/10.1038/ncb2113"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20953199"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20953199"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Tarek Abbas, Etsuko Shibata, Jonghoon Park, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CRL4(Cdt2) regulates cell proliferation and histone gene expression by targeting PR-Set7/Set8 for degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2010.09.014"}], "href": "https://doi.org/10.1016/j.molcel.2010.09.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20932471"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20932471"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Hisanobu Oda, Michael R Hübner, David B Beck, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of the histone H4 monomethylase PR-Set7 by CRL4(Cdt2)-mediated PCNA-dependent degradation during DNA damage."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2010.10.011"}], "href": "https://doi.org/10.1016/j.molcel.2010.10.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21035370"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21035370"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Richard C Centore, Courtney G Havens, Amity L Manning, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CRL4(Cdt2)-mediated destruction of the histone methyltransferase Set8 prevents premature chromatin compaction in S phase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2010.09.015"}], "href": "https://doi.org/10.1016/j.molcel.2010.09.015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20932472"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20932472"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Xiaobing Shi, Ioulia Kachirskaia, Hiroshi Yamaguchi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Modulation of p53 function by SET8-mediated methylation at lysine 382."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2007.07.012"}], "href": "https://doi.org/10.1016/j.molcel.2007.07.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17707234"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17707234"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Hisanobu Oda, Ikuhiro Okamoto, Niall Murphy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Monomethylation of histone H4-lysine 20 is involved in chromosome structure and stability and is essential for mouse development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.01768-08"}], "href": "https://doi.org/10.1128/MCB.01768-08"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19223465"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19223465"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Stine Jørgensen, Ingegerd Elvers, Morten Beck Trelle, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The histone methyltransferase SET8 is required for S-phase progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.200706150"}], "href": "https://doi.org/10.1083/jcb.200706150"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18166648"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18166648"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Jean-François Couture, Evys Collazo, Joseph S Brunzelle, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural and functional analysis of SET8, a histone H4 Lys-20 methyltransferase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.1318405"}], "href": "https://doi.org/10.1101/gad.1318405"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15933070"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15933070"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Ken-ichi Wakabayashi, Masashi Okamura, Shuichi Tsutsumi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The peroxisome proliferator-activated receptor gamma/retinoid X receptor alpha heterodimer targets the histone modification enzyme PR-Set7/Setd8 gene and regulates adipogenesis through a positive feedback loop."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.01856-08"}], "href": "https://doi.org/10.1128/MCB.01856-08"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19414603"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19414603"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Zhenfei Li, Fen Nie, Sheng Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Histone H4 Lys 20 monomethylation by histone methylase SET8 mediates Wnt target gene activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1009353108"}], "href": "https://doi.org/10.1073/pnas.1009353108"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21282610"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21282610"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Masashi Takawa, Hyun-Soo Cho, Shinya Hayami, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Histone lysine methyltransferase SETD8 promotes carcinogenesis by deregulating PCNA expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-11-3701"}], "href": "https://doi.org/10.1158/0008-5472.CAN-11-3701"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22556262"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22556262"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Lourdes Serrano, Paloma Martínez-Redondo, Anna Marazuela-Duque, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The tumor suppressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.211342.112"}], "href": "https://doi.org/10.1101/gad.211342.112"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23468428"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23468428"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Fen Yang, Luyang Sun, Qian Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SET8 promotes epithelial-mesenchymal transition and confers TWIST dual transcriptional activities."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/emboj.2011.364"}], "href": "https://doi.org/10.1038/emboj.2011.364"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21983900"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21983900"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "N Kalakonda, W Fischle, P Boccuni, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Histone H4 lysine 20 monomethylation promotes transcriptional repression by L3MBTL1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2008.67"}], "href": "https://doi.org/10.1038/onc.2008.67"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18408754"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18408754"}]}]}]}