ANALYSIS OF GENOMIC INFORMATION 14 15 16 17 18 19 20 21 22 23 24 25 26 1284 likely GTPases as indicated by the activity of CIITA and HET E E V Koonin L Aravind Trends Biochem Sci 25 223 2000 T L Beattie W Zhou M O Robinson L Harrington Curr Biol 8 177 1998 E Diez Z Yaraghi A MacKenzie P Gros J Immunol 164 1470 2000 A M Verhagen et al Cell 102 43 2000 L Goyal K McCall J Agapite E Hartwieg H Steller EMBO J 19 589 2000 The eukaryotic crown group is the assemblage of relatively late diverging major eukaryotic taxa whose exact order of radiation is difficult to determine with confidence The crown group includes the multicellular eukaryotes animals fungi and plants and some unicellular eukaryotic lineages such as slime molds and Acanthamoebae A H Knoll Science 256 622 1992 S Kumar A Rzhetsky J Mol Evol 42 183 1996 The sister group of the classic animal caspase family of thiol proteases are the paracaspases that thus far have been identified only in animals and Dictyostelium together these two families constitute the sister group of the metacaspases that have been detected in plants protists and bacteria A G Uren et al Mol Cell 6 961 2000 On the basis of conserved structural features Uren et al showed that the paracaspases and metacaspases are specifically related to the caspases to the exclusion of other members of the caspase gingipain fold A Eichinger et al EMBO J 18 5453 1999 The A20 protein is a regulator of apoptosis that appears to be involved in the NF B pathway and interactions with the TRAFs R Beyaert K Heyninck S Van Huffel Biochem Pharmacol 60 1143 2000 A20 belongs to a distinct family of predicted thiol proteases that is conserved in all crown group eukaryotes and many viruses None of the members of this family has a known biochemical function but they share two conserved motifs with the cysteine proteases of arteriviruses which led to the prediction of the protease activity A20 and another protein of this family cezanne contain a specialized finger module that is also found in some proteins of the ubiquitin pathway Together with a fusion of an A20 like protease domain with a ubiquitin hydrolase that has been detected in C elegans this suggests a functional connection between these predicted proteases and the ubiquitin system K S Makarova L Aravind E V Koonin Trends Biochem Sci 25 50 2000 An additional connection between apoptosis and the ubiquitin system is indicated by the demonstration that similar to other RING fingers the one in TRAF6 is an E3 like ubiquitin ligase pathway L Deng et al Cell 103 351 2000 The AP GTPase is a previously undetected predicted GTPase typified by the COOH terminal domain of the conserved apoptosis regulator the DAP protein kinase B Inbal et al Nature 390 180 1997 This predicted GTPase family appears to be the sister group of the RAS ARF family GTPases but differs from them in having a divergent P loop motif and a THXD instead of the NKXD signature motif Additional AP GTPases are found in plants and animals as multidomain proteins that also contain ankyrin Lrr and kinase domains This domain architecture suggests that AP GTPases participate in GTP dependent assembly of signaling complexes A G Uren et al Proc Natl Acad Sci U S A 96 10170 1999 The ZU5 domain is a previously undetected conserved domain that is present in receptors such as netrin receptors and vertebrate zona pellucida proteins and cytoskeletal proteins such as ankyrins and is predicted to be involved in anchoring receptors to the cytoskeleton S L Ackerman B B Knowles Genomics 52 205 1998 H Sakahira M Enari S Nagata Nature 391 96 1998 A M Aguinaldo et al Nature 387 489 1997 27 L Aravind H Watanabe D J Lipman E V Koonin Proc Natl Acad Sci U S A 97 11319 2000 28 J R Brown W F Doolittle Microbiol Mol Biol Rev 61 456 1997 29 We thank E Birney and A Bateman The Sanger Center Hinxton UK for kindly providing the preliminary version of the Integrated Protein Index and A Uren for critical reading of the manuscript and useful comments The release of the unpublished WormPep data set by The Sanger Center is acknowledged and greatly appreciated 25 October 2000 accepted 18 January 2001 Human DNA Repair Genes Richard D Wood 1 Michael Mitchell 2 John Sgouros 2 Tomas Lindahl1 Cellular DNA is subjected to continual attack both by reactive species inside cells and by environmental agents Toxic and mutagenic consequences are minimized by distinct pathways of repair and 130 known human DNA repair genes are described here Notable features presently include four enzymes that can remove uracil from DNA seven recombination genes related to RAD51 and many recently discovered DNA polymerases that bypass damage but only one system to remove the main DNA lesions induced by ultraviolet light More human DNA repair genes will be found by comparison with model organisms and as common folds in three dimensional protein structures are determined Modulation of DNA repair should lead to clinical applications including improvement of radiotherapy and treatment with anticancer drugs and an advanced understanding of the cellular aging process The human genome like other genomes encodes information to protect its own integrity 1 DNA repair enzymes continuously monitor chromosomes to correct damaged nucleotide residues generated by exposure to carcinogens and cytotoxic compounds The damage is partly a consequence of environmental agents such as ultraviolet UV light from the sun inhaled cigarette smoke or incompletely defined dietary factors However a large proportion of DNA alterations are caused unavoidably by endogenous weak mutagens including water reactive oxygen species and metabolites that can act as alkylating agents Very slow turnover of DNA consequently occurs even in cells that do not proliferate Genome instability caused by the great variety of DNA damaging agents would be an overwhelming problem for cells and organisms if it were not for DNA repair On the basis of searches of the current draft of the human genome sequence 2 we compiled a comprehensive list of DNA repair genes Table 1 This inventory focuses on genes whose products have been functionally linked to the recognition and repair of damaged DNA as well as those showing strong sequence homology to repair genes in other organisms Readers desiring further information on specific genes should consult the primary references and links available 1 Imperial Cancer Research Fund Clare Hall Laboratories Blanche Lane South Mimms Herts EN6 3LD UK 2 Imperial