RAD1 homolog explained

Cell cycle checkpoint protein RAD1 is a protein that in humans is encoded by the RAD1 gene.^{[1] [2] [3]}

Function

This gene encodes a component of a heterotrimeric cell cycle checkpoint complex, known as the 9-1-1 complex, that is activated to stop cell cycle progression in response to DNA damage or incomplete DNA replication. The 9-1-1 complex is recruited by RAD17 to affected sites where it may attract specialized DNA polymerases and other DNA repair effectors. Alternatively spliced transcript variants encoding different isoforms of this gene have been described.^[3]

Meiosis

During meiosis, double-strand breaks occur in DNA that initiate recombination. Recombination is a process that repairs the breaks and also promotes faithful chromosome segregation.^[4] In yeast the 9-1-1 complex (including RAD1) facilitates meiotic recombination. An alternative, but inaccurate, mechanism for repairing double-strand breaks is non-homologous end joining. In the rice plant, the 9-1-1 complex promotes accurate meiotic recombination by suppressing the alternative process of non-homologous end joining.^[4]

During mammalian meiosis 9-1-1 complexes promote synapsis of homologous chromosomes.^[5] Testis-specific disruption of RAD1 in mice results in defective double-strand break repair, depletion of germ cells and infertility.^[5]

Interactions

RAD1 homolog has been shown to interact with:

• HUS1,^[6]
• RAD17,^{[7] [8] [9]} and
• RAD9A,^{[10] [11] [12] [13] [14]}

Further reading

• Bardwell AJ, Bardwell L, Johnson DK, Friedberg EC . Yeast DNA recombination and repair proteins Rad1 and Rad10 constitute a complex in vivo mediated by localized hydrophobic domains. . Mol. Microbiol. . 8 . 6 . 1177–88 . 1993 . 8361362 . 10.1111/j.1365-2958.1993.tb01662.x . 45135386 .
• Parker AE, Van de Weyer I, Laus MC, Oostveen I, Yon J, Verhasselt P, Luyten WH . A human homologue of the Schizosaccharomyces pombe rad1+ checkpoint gene encodes an exonuclease. . J. Biol. Chem. . 273 . 29 . 18332–9 . 1998 . 9660799 . 10.1074/jbc.273.29.18332 . 24604811 . free .
• Udell CM, Lee SK, Davey S . HRAD1 and MRAD1 encode mammalian homologues of the fission yeast rad1(+) cell cycle checkpoint control gene. . Nucleic Acids Res. . 26 . 17 . 3971–6 . 1998 . 9705507 . 147814 . 10.1093/nar/26.17.3971 .
• Marathi UK, Dahlen M, Sunnerhagen P, Romero AV, Ramagli LS, Siciliano MJ, Li L, Legerski RJ . RAD1, a human structural homolog of the Schizosaccharomyces pombe RAD1 cell cycle checkpoint gene. . Genomics . 54 . 2 . 344–7 . 1999 . 9828139 . 10.1006/geno.1998.5589 .
• Volkmer E, Karnitz LM . Human homologs of Schizosaccharomyces pombe rad1, hus1, and rad9 form a DNA damage-responsive protein complex. . J. Biol. Chem. . 274 . 2 . 567–70 . 1999 . 9872989 . 10.1074/jbc.274.2.567 . 28787137 . free .
• Dean FB, Lian L, O'Donnell M . cDNA cloning and gene mapping of human homologs for Schizosaccharomyces pombe rad17, rad1, and hus1 and cloning of homologs from mouse, Caenorhabditis elegans, and Drosophila melanogaster. . Genomics . 54 . 3 . 424–36 . 1999 . 9878245 . 10.1006/geno.1998.5587 .
• St Onge RP, Udell CM, Casselman R, Davey S . The human G2 checkpoint control protein hRAD9 is a nuclear phosphoprotein that forms complexes with hRAD1 and hHUS1. . Mol. Biol. Cell . 10 . 6 . 1985–95 . 1999 . 10359610 . 25401 . 10.1091/mbc.10.6.1985 .
• Hang H, Lieberman HB . Physical interactions among human checkpoint control proteins HUS1p, RAD1p, and RAD9p, and implications for the regulation of cell cycle progression. . Genomics . 65 . 1 . 24–33 . 2000 . 10777662 . 10.1006/geno.2000.6142 . free .
• Cai RL, Yan-Neale Y, Cueto MA, Xu H, Cohen D . HDAC1, a histone deacetylase, forms a complex with Hus1 and Rad9, two G2/M checkpoint Rad proteins. . J. Biol. Chem. . 275 . 36 . 27909–16 . 2000 . 10846170 . 10.1074/jbc.M000168200 . free .
• Burtelow MA, Kaufmann SH, Karnitz LM . Retention of the human Rad9 checkpoint complex in extraction-resistant nuclear complexes after DNA damage. . J. Biol. Chem. . 275 . 34 . 26343–8 . 2000 . 10852904 . 10.1074/jbc.M001244200 . 24638557 . free .
• Rauen M, Burtelow MA, Dufault VM, Karnitz LM . The human checkpoint protein hRad17 interacts with the PCNA-like proteins hRad1, hHus1, and hRad9. . J. Biol. Chem. . 275 . 38 . 29767–71 . 2000 . 10884395 . 10.1074/jbc.M005782200 . 34505615 . free .
• Burtelow MA, Roos-Mattjus PM, Rauen M, Babendure JR, Karnitz LM . Reconstitution and molecular analysis of the hRad9-hHus1-hRad1 (9-1-1) DNA damage responsive checkpoint complex. . J. Biol. Chem. . 276 . 28 . 25903–9 . 2001 . 11340080 . 10.1074/jbc.M102946200 . 25624886 . free .
• Bao S, Tibbetts RS, Brumbaugh KM, Fang Y, Richardson DA, Ali A, Chen SM, Abraham RT, Wang XF . ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses. . Nature . 411 . 6840 . 969–74 . 2001 . 11418864 . 10.1038/35082110 . 4429058 .
• Xiang SL, Kumano T, Iwasaki SI, Sun X, Yoshioka K, Yamamoto KC . The J domain of Tpr2 regulates its interaction with the proapoptotic and cell-cycle checkpoint protein, Rad9. . Biochem. Biophys. Res. Commun. . 287 . 4 . 932–40 . 2001 . 11573955 . 10.1006/bbrc.2001.5685 . 2297/1794 . 20694221 . free .
• Zou L, Cortez D, Elledge SJ . Regulation of ATR substrate selection by Rad17-dependent loading of Rad9 complexes onto chromatin. . Genes Dev. . 16 . 2 . 198–208 . 2002 . 11799063 . 155323 . 10.1101/gad.950302 .
• Griffith JD, Lindsey-Boltz LA, Sancar A . Structures of the human Rad17-replication factor C and checkpoint Rad 9-1-1 complexes visualized by glycerol spray/low voltage microscopy. . J. Biol. Chem. . 277 . 18 . 15233–6 . 2002 . 11907025 . 10.1074/jbc.C200129200 . 24820773 . free .
• Hang H, Zhang Y, Dunbrack RL, Wang C, Lieberman HB . Identification and characterization of a paralog of human cell cycle checkpoint gene HUS1. . Genomics . 79 . 4 . 487–92 . 2002 . 11944979 . 10.1006/geno.2002.6737 .
• Hirai I, Wang HG . A role of the C-terminal region of human Rad9 (hRad9) in nuclear transport of the hRad9 checkpoint complex. . J. Biol. Chem. . 277 . 28 . 25722–7 . 2002 . 11994305 . 10.1074/jbc.M203079200 . 35202138 . free .

Notes and References

1. Freire R, Murguía JR, Tarsounas M, Lowndes NF, Moens PB, Jackson SP . Human and mouse homologs of Schizosaccharomyces pombe rad1(+) and Saccharomyces cerevisiae RAD17: linkage to checkpoint control and mammalian meiosis . Genes Dev . 12 . 16 . 2560–73 . September 1998 . 9716408 . 317084 . 10.1101/gad.12.16.2560 .
2. Bluyssen HA, van Os RI, Naus NC, Jaspers I, Hoeijmakers JH, de Klein A . A human and mouse homolog of the Schizosaccharomyces pombe rad1+ cell cycle checkpoint control gene . Genomics . 54 . 2 . 331–7 . January 1999 . 9828137 . 10.1006/geno.1998.5582 .
3. Web site: Entrez Gene: RAD1 RAD1 homolog (S. pombe).
4. Hu Q, Tang D, Wang H, Shen Y, Chen X, Ji J, Du G, Li Y, Cheng Z. The Exonuclease Homolog OsRAD1 Promotes Accurate Meiotic Double-Strand Break Repair by Suppressing Nonhomologous End Joining. Plant Physiol. 2016 Oct;172(2):1105-1116. doi: 10.1104/pp.16.00831. Epub 2016 Aug 10. PMID: 27512017; PMCID: PMC5047095
5. Pereira C, Arroyo-Martinez GA, Guo MZ, Downey MS, Kelly ER, Grive KJ, Mahadevaiah SK, Sims JR, Faca VM, Tsai C, Schiltz CJ, Wit N, Jacobs H, Clark NL, Freire R, Turner J, Lyndaker AM, Brieno-Enriquez MA, Cohen PE, Smolka MB, Weiss RS. Multiple 9-1-1 complexes promote homolog synapsis, DSB repair, and ATR signaling during mammalian meiosis. Elife. 2022 Feb 8;11:e68677. doi: 10.7554/eLife.68677. PMID: 35133274; PMCID: PMC8824475
6. Hang H, Zhang Y, Dunbrack RL, Wang C, Lieberman HB . Identification and characterization of a paralog of human cell cycle checkpoint gene HUS1 . Genomics . 79 . 4 . 487–92 . April 2002 . 11944979 . 10.1006/geno.2002.6737 .
7. Bermudez VP, Lindsey-Boltz LA, Cesare AJ, Maniwa Y, Griffith JD, Hurwitz J, Sancar A . Loading of the human 9-1-1 checkpoint complex onto DNA by the checkpoint clamp loader hRad17-replication factor C complex in vitro . Proc. Natl. Acad. Sci. U.S.A. . 100 . 4 . 1633–8 . February 2003 . 12578958 . 149884 . 10.1073/pnas.0437927100 . 2003PNAS..100.1633B . free .
8. Rauen M, Burtelow MA, Dufault VM, Karnitz LM . The human checkpoint protein hRad17 interacts with the PCNA-like proteins hRad1, hHus1, and hRad9 . J. Biol. Chem. . 275 . 38 . 29767–71 . September 2000 . 10884395 . 10.1074/jbc.M005782200 . 34505615 . free .
9. Bao S, Tibbetts RS, Brumbaugh KM, Fang Y, Richardson DA, Ali A, Chen SM, Abraham RT, Wang XF . ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses . Nature . 411 . 6840 . 969–74 . June 2001 . 11418864 . 10.1038/35082110 . 4429058 .
10. Volkmer E, Karnitz LM . Human homologs of Schizosaccharomyces pombe rad1, hus1, and rad9 form a DNA damage-responsive protein complex . J. Biol. Chem. . 274 . 2 . 567–70 . January 1999 . 9872989 . 10.1074/jbc.274.2.567. 28787137 . free .
11. Dufault VM, Oestreich AJ, Vroman BT, Karnitz LM . Identification and characterization of RAD9B, a paralog of the RAD9 checkpoint gene . Genomics . 82 . 6 . 644–51 . Dec 2003 . 14611806 . 10.1016/s0888-7543(03)00200-3.
12. Griffith JD, Lindsey-Boltz LA, Sancar A . Structures of the human Rad17-replication factor C and checkpoint Rad 9-1-1 complexes visualized by glycerol spray/low voltage microscopy . J. Biol. Chem. . 277 . 18 . 15233–6 . May 2002 . 11907025 . 10.1074/jbc.C200129200 . 24820773 . free .
13. Hirai I, Wang HG . A role of the C-terminal region of human Rad9 (hRad9) in nuclear transport of the hRad9 checkpoint complex . J. Biol. Chem. . 277 . 28 . 25722–7 . July 2002 . 11994305 . 10.1074/jbc.M203079200 . 35202138 . free .
14. Lindsey-Boltz LA, Bermudez VP, Hurwitz J, Sancar A . Purification and characterization of human DNA damage checkpoint Rad complexes . Proc. Natl. Acad. Sci. U.S.A. . 98 . 20 . 11236–41 . September 2001 . 11572977 . 58713 . 10.1073/pnas.201373498 . 2001PNAS...9811236L . free .