Editing Xeroderma pigmentosum (section)

===XP repair proteins===

The [[XPA]] protein acts during NER as a scaffold for assembly of other [[DNA repair]] proteins at sites of [[DNA damage (naturally occurring)|DNA damage]] to ensure appropriate excision of the damage.<ref name="pmid27247238">{{Cite journal |vauthors=Sugitani N, Sivley RM, Perry KE, Capra JA, Chazin WJ |date=August 2016 |title=XPA: A key scaffold for human nucleotide excision repair |journal=DNA Repair |volume=44 |pages=123–135 |doi=10.1016/j.dnarep.2016.05.018 |pmc=4958585 |pmid=27247238}}</ref>

The [[XPB]] (ERCC3) protein is employed in unwinding the [[DNA]] double helix after DNA damage is initially recognized. [[Mutation]]s in the ''XPB(ERCC3)'' gene can lead to XP or XP combined with [[Cockayne syndrome]].<ref name="pmid16947863">{{Cite journal |vauthors=Oh KS, Khan SG, Jaspers NG, Raams A, Ueda T, Lehmann A, Friedmann PS, Emmert S, Gratchev A, Lachlan K, Lucassan A, Baker CC, Kraemer KH |date=November 2006 |title=Phenotypic heterogeneity in the XPB DNA helicase gene (ERCC3): xeroderma pigmentosum without and with Cockayne syndrome |journal=Human Mutation |volume=27 |issue=11 |pages=1092–103 |doi=10.1002/humu.20392 |pmid=16947863 |s2cid=22852219 |doi-access=free}}</ref>

The [[XPC (gene)|XPC]] protein forms a complex with [[RAD23B]] protein to form the initial damage recognition factor in global genomic [[nucleotide excision repair]] (GG-NER).<ref name="pmid9734359">{{Cite journal |vauthors=Sugasawa K, Ng JM, Masutani C, Iwai S, van der Spek PJ, Eker AP, Hanaoka F, Bootsma D, Hoeijmakers JH |date=August 1998 |title=Xeroderma pigmentosum group C protein complex is the initiator of global genome nucleotide excision repair |journal=Molecular Cell |volume=2 |issue=2 |pages=223–32 |doi=10.1016/s1097-2765(00)80132-x |pmid=9734359 |doi-access=free}}</ref> This complex recognizes a wide variety of damages that thermodynamically destabilize DNA duplexes.{{citation needed|date=October 2020}}

The XPD ([[ERCC2]]) protein, in combination with the XPB helicase-containing transcription/repair complex [[Transcription factor II H|TFIIH]], is employed in unwinding the DNA duplex after damage is initially recognized. Mutations in the ''XPD(ERCC2)'' gene cause a variety of syndromes; XP, [[trichothiodystrophy]] (TTD), or a combination of XP and Cockayne syndrome (XPCS).<ref name="pmid17172862">{{Cite journal |vauthors=Andressoo JO, Hoeijmakers JH, Mitchell JR |date=December 2006 |title=Nucleotide excision repair disorders and the balance between cancer and aging |journal=Cell Cycle |volume=5 |issue=24 |pages=2886–8 |doi=10.4161/cc.5.24.3565 |pmid=17172862 |s2cid=43682426}}</ref><ref name="pmid23046824">{{Cite journal |vauthors=van de Ven M, Andressoo JO, van der Horst GT, Hoeijmakers JH, Mitchell JR |date=November 2012 |title=Effects of compound heterozygosity at the Xpd locus on cancer and ageing in mouse models |journal=DNA Repair |volume=11 |issue=11 |pages=874–83 |doi=10.1016/j.dnarep.2012.08.003 |pmid=23046824}}</ref> Both trichothiodystrophy and Cockayne syndrome display features of premature aging, suggesting an association between deficient DNA repair and premature aging .{{cn|date=October 2024}}

XPE is a heterodimeric protein composed of two subunits. The larger subunit [[DDB1]] primarily functions as a core component of [[CUL4A]]- and [[CUL4B]]-based E3 [[ubiquitin]] ligase complexes. Substrates that are ubiquitinnated by these complexes include proteins employed in DNA repair.<ref name="pmid21959250">{{Cite journal |vauthors=Iovine B, Iannella ML, Bevilacqua MA |date=December 2011 |title=Damage-specific DNA binding protein 1 (DDB1): a protein with a wide range of functions |journal=The International Journal of Biochemistry & Cell Biology |volume=43 |issue=12 |pages=1664–7 |doi=10.1016/j.biocel.2011.09.001 |pmid=21959250}}</ref>

The XPF ([[ERCC4]]) protein together with the [[ERCC1]] protein forms a complex usually designated ERCC1-XPF. This complex separates the DNA helix for a short distance on either side of the site of damage. It then acts as an [[endonuclease]] to incise the damaged DNA strand on the 5' side of the damaged site.<ref name="pmid8797827">{{Cite journal |vauthors=Sijbers AM, de Laat WL, Ariza RR, Biggerstaff M, Wei YF, Moggs JG, Carter KC, Shell BK, Evans E, de Jong MC, Rademakers S, de Rooij J, Jaspers NG, Hoeijmakers JH, Wood RD |date=September 1996 |title=Xeroderma pigmentosum group F caused by a defect in a structure-specific DNA repair endonuclease |journal=Cell |volume=86 |issue=5 |pages=811–22 |doi=10.1016/s0092-8674(00)80155-5 |pmid=8797827 |s2cid=12957716 |hdl-access=free |hdl=1765/3110}}</ref> Mutant cells with deficient ERCC1-XPF are not only defective in NER, but also in the repair of double-strand breaks and inter-strand crosslinks.{{cn|date=October 2024}}

The XPG protein is an endonuclease that incises DNA during NER at the 3' side of the damaged nucleotide. Mutations in the ''XPG ([[ERCC5]])'' gene can lead to XP alone, or in combination with Cockayne syndrome (CS), or in combination with infantile lethal cerebro-oculo-facio-skeletal syndrome.<ref name="pmid25299392">{{Cite journal |vauthors=Barnhoorn S, Uittenboogaard LM, Jaarsma D, Vermeij WP, Tresini M, Weymaere M, Menoni H, Brandt RM, de Waard MC, Botter SM, Sarker AH, Jaspers NG, van der Horst GT, Cooper PK, Hoeijmakers JH, van der Pluijm I |date=October 2014 |title=Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency |journal=PLOS Genetics |volume=10 |issue=10 |pages=e1004686 |doi=10.1371/journal.pgen.1004686 |pmc=4191938 |pmid=25299392 |doi-access=free}}</ref>