Table S1. Candidate genes selected for the study of intergenerational instability in families with Machado-Joseph disease
Gene name / Main activity / Accession numberMismatch excision repair (MMR)
MSH2 / Mismatch (MSH2-MSH6) and loop (MSH2-MSH3) recognition / NM_000251
MSH3 / NM_002439
MSH6 / NM_000179
MSH4 / Involved in meiotic recombination / NM_002440
MSH5 / NM_002441
PMS1 / Probably involved in the repair of DNA mismatches / NM_000534
PMS2 / Component of the post-replicative DNA MMR system / NM_000535
PMS2P3 / MutL homologue / NM_005395
PMS2P4 / PMS1 homologue / NR_046297
MLH1 / Heterodimerizes with PMS2 to form MutL alpha / NM_000249
MLH3 / Probably involved in the repair of DNA mismatches / NM_014381
Base excision repair (BER)
DNA glycosylases
UNG / Excises uracil residues from the DNA / NM_080911
SMUG1 / Recognizes base lesions in the genome and initiates base excision DNA repair / NM_014311
MBD4 / Mismatch-specific DNA N-glycosylase / NM_003925
TDG / Hydrolyzes mismatched dsDNA and polynucleotides / NM_003211
OGG1 / Incises DNA at 8-oxoG residues / NM_016821
MUTYH / Involved in oxidative DNA damage repair / NM_012222
NTHL1 / Has bothapurinic and/or apyrimidinic endonuclease activity and a DNA N-glycosylase activity / NM_002528
MPG / Hydrolysis of the deoxyribose N-glycosidic bond to excise 3-methyladenine, and 7-methylguanine from thedamaged DNA polymer formed by alkylation lesions / NM_002434
NEIL1 / Recognizes and removes damaged bases of DNA damaged by oxidation or mutagenic agents / NM_024608
NEIL2 / Has DNA glycosylaseactivity towards 5-hydroxyuracil and other oxidized derivatives of cytosine with a preference for mismatched dsDNA / NM_145043
NEIL3 / Removes oxidative products of pyrimidines / NM_018248
Other BER factors
APEX1 / Plays a central role in the cellular response to oxidative stress; apurinic/apyrimidinic (AP) endonuclease / NM_001641
APEX2 / Initiates repair of AP sites / NM_014481
LIG3 / Interacts with XRCC1 and can correct defective DSB repair and sisterchromatid exchange / NM_013975
XRCC1 / Ligase accessory factor / NM_006297
PNKP / Part of both NHEJ and BER pathways; converts some DNA breaks to ligatable ends / NM_007254
Nucleotide excision repair (NER)
XPC / Acts as damage sensing and DNA-bindingfactor component of the XPC complex / NM_004628
RAD23B / Multiubiquitin chain receptor involved in the modulation of proteasomal degradation / NM_002874
CETN2 / Plays a fundamental role in microtubule-organizing center structure and function / NM_004344
RAD23A / Multiubiquitin chain receptor involved in the modulation of proteasomal degradation; substitutes for HR23B / NM_005053
XPA / Binds damaged DNA in preincision complex / NM_000380
DDB1 / Binds to DDB2 to form the UV-damaged DNA-binding protein complex / NM_001923
DDB2 / Binds to DDB1 to form the UV-damaged DNA-binding protein complex / NM_000107
RPA1 / Essential in DNA replication, recombinationand repair; binds and subsequently stabilizes ssDNA intermediates and thus prevents complementaryDNA from reannealing / NM_002945
RPA2 / Required for the efficient recruitment of the DNA double-strand break (DSB) repairfactor RAD51 to chromatin in response to DNA damage / NM_002946
RPA3 / Required for DNA recombination, repair and replication / NM_002947
TFIIH: Catalyzes unwinding in preincision complex
ERCC2 / 5' to 3' DNA helicase / NM_000400
ERCC3 / NM_000122
GTF2H1 / Component of the core-TFIIH basal transcription factor / NM_005316
GTF2H3 / NM_001516
GTF2H4 / NM_001517
GTF2H5 / NM_207118
CDK7 / Serine/threonine kinase involved in cell cycle control and in RNA polymerase II-mediated RNA transcription / NM_001799
CCNH / Regulates CDK7 / NM_001239
MNAT1 / Stabilizes the CCNH-CDK7 complex to form a functional CDK-activating kinase enzymatic complex / NM_002431
ERCC5 / Single-stranded structure-specific DNA endonuclease (makes the 3'incision inDNA) / NM_000123
ERCC1 / Endonuclease responsible for the 5' incision DNA binding subunit / NM_001983
ERCC4 / Structure-specific DNA repair endonuclease responsible for the 5’ incision during repair; involvedin homologous recombination that assists in removing interstrand cross-link / NM_005236
LIG1 / DNA ligase that seals nicks in dsDNA during replication, recombination and repair / NM_000234
NER-related
ERCC8 / Substrate-recognition component of the CSA complex / NM_000082
ERCC6 / Allows RNA polymeraseII-blocking lesions to be removed from the transcribed strand of active genes; upon DNA-binding, it locallymodifies DNA conformation by wrapping the DNA around itself, modifying the interface between stalled RNApolymerase II and DNA / NM_000124
XAB2 / Involved in transcription-coupled repair, transcription and pre-mRNA splicing / NM_020196
MMS19 / May play a role in NER and RNA polymerase II transcription byinteracting with ERCC2 and ERCC3 helicases / NM_022362
Other identified genes with a suspected DNA repair function
DCLRE1A / May be required for DNA interstrand cross-link repair / NM_014881
DCLRE1B / 5'-3' exonuclease that plays a central role in telomere maintenance and protection during S-phase / NM_022836
RPA4 / Component of the alternative replication protein A complex, which binds ssDNA / NM_013347
RECQL / DNA helicase (unwinds ssDNA and dsDNA in a 3'-5' direction) / NM_002907
RECQL5 / DNA helicase / NM_001003715
HELQ / 5' to 3' DNA helicase / NM_133636
RDM1 / Similar to RAD52; binds to DNA and RNA / NM_145654
Editing and processing nucleases
FEN1 / Structure-specific nuclease with 5'-flap endonuclease and 5'-3' exonuclease activities involved in DNAreplication and repair / NM_004111
EXO1 / 5'-3' dsDNAexonucleasewith a possible cryptic 3'-5' dsDNAexonuclease activity / NM_003686
SPO11 / Required for meiotic recombination; mediates DNA cleavage that forms the DSB toinitiate meiotic recombination (by similarity) / NM_012444
APTX / DNA-binding protein involved in ssDNA break repair, DSB repair and BER / NM_175073
DNA polymerases (catalytic subunits)
POLG / Involved in the replication of mtDNA / NM_002693
POLD1 / Possesses two enzymatic activities: DNA synthesis (polymerase) and an exonucleolytic activity that degradesssDNA in the 3'- to 5'-direction / NM_002691
POLE / Participates in DNA repair and in chromosomal DNA replication / NM_006231
PCNA / Auxiliary protein of DNA polymerase delta involved in the control of eukaryotic DNAreplication by increasing the polymerase processibility during elongation of the leading strand / NM_002592
REV3L / Interacts with MAD2L2 to form the error prone DNA polymerase zeta involved in translesion DNA synthesis / NM_002912
POLA1 / Essential in the initiation of DNA replication / NM_016937.3
Other conserved DNA damage response genes
RAD1 / Subunits of PCNA-like sensor of damagedDNA / NM_002853
RAD9A / NM_004584
RAD17 / Essential for sustained cell growth, maintenance of chromosomal stability / NM_002873
TP53 / Regulation of the cell cycle / NM_000546
ATRIP / Required for checkpoint signaling after DNA damage / NM_130384
Homologous recombination
RAD51 / Homologous pairing; binds to ssDNA and dsDNA / NM_002875
RAD52 / Involved in DSB repair; promotes the annealing of complementary ssDNA and stimulates the RAD51 recombinase / NM_002879
RAD54L / Involved in DNA repair and mitotic recombination; functions in the recombinational DNA repairpathway / NM_003579
RAD50 / Component of the MRN complex, which plays a central role in DSB repair, DNArecombination, maintenance of telomere integrity and meiosis / NM_005732
MRE11A / NM_005590
MUS81 / Interacts with EME1 and EME2 to form a DNA structure-specific endonuclease with substrate preference forbranched DNA structures with a 5'-end at the branch nick / NM_025128
Others
PRKDC / Involved in non-homologous end-joining repair; DNA-dependent protein kinase catalytic subunit / NM_006904
WRN / Multifunctional enzyme that has both magnesium and ATP-dependent DNA-helicase activity and 3'-5' exonucleaseactivity towards dsDNA with a 5'-overhang / NM_000553.4
ATM / Serine/threonine protein kinase that activates checkpoint signaling upon DSBs / NM_000051
BLM / DNA-helicase; unwinds ssDNAand dsDNA in a 3'-5' direction / NM_000057.2
RFC1 / May play a role in DNA transcription, regulation and DNA replication and/or repair; can bind ssDNA and dsDNA / NM_002913.4
RNaseH1 / Endonuclease that specifically degrades the RNA of RNA-DNA hybrids / NM_002936.3
DNA2 / May function in chromosomal DNA replication (by similarity) / NM_001080449.2
PRIM1 / Polymerase that synthesizes small RNA primers for the Okazaki fragments made duringdiscontinuous DNA replication / NM_000946.2
CLSPN / Required for checkpoint mediated cell cycle arrest in response to inhibition of DNA replication / NM_022111.3
CDK7PS / Cyclin-dependent kinase 7pseudogene / NG_001572.4
CHEK2 / Serine/threonine-protein kinase required for checkpoint-mediated cell cycle arrest, activation ofDNA repair and apoptosis in response to the presence of DSBs / NM_007194.3