Editing Downregulation and upregulation (section)

==Cancer==
{{See also|Regulation of transcription in cancer}}
DNA damage appears to be the primary underlying cause of cancer.<ref name=BernsteinPrasad>{{cite book |last1= Bernstein |first1=C |last2=Prasad |first2=AR |last3=Nfonsam |first3=V |last4=Bernstein |first4=H. |year=2013 |chapter= Chapter 16: DNA Damage, DNA Repair and Cancer |title= New Research Directions in DNA Repair |editor-first=Clark |editor-last=Chen |isbn=978-953-51-1114-6|page=413|publisher=BoD – Books on Demand }}</ref> DNA damage can also increase [[epigenetic]] alterations due to errors during DNA repair.<ref name="O'Hagan2008">{{cite journal |last1=O'Hagan |first1=Heather M. |last2=Mohammad |first2=Helai P. |last3=Baylin |first3=Stephen B. |title=Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an Exogenous Promoter CpG Island |journal=PLOS Genetics |date=15 August 2008 |volume=4 |issue=8 |pages=e1000155 |doi=10.1371/journal.pgen.1000155 |pmid=18704159 |pmc=2491723 |doi-access=free |quote=Taken together, our data suggest that normal repair of a DNA break can occasionally cause heritable silencing of a CpG island–containing promoter by recruitment of proteins involved in silencing...This finding suggests that DNA damage may directly contribute to the large number of epigenetically silenced genes in tumors. }}</ref><ref name="Cuozzo2007">{{cite journal |last1=Cuozzo |first1=Concetta |last2=Porcellini |first2=Antonio |last3=Angrisano |first3=Tiziana |last4=Morano |first4=Annalisa |last5=Lee |first5=Bongyong |last6=Pardo |first6=Alba Di |last7=Messina |first7=Samantha |last8=Iuliano |first8=Rodolfo |last9=Fusco |first9=Alfredo |last10=Santillo |first10=Maria R |last11=Muller |first11=Mark T |last12=Chiariotti |first12=Lorenzo |last13=Gottesman |first13=Max E |last14=Avvedimento |first14=Enrico V |title=DNA Damage, Homology-Directed Repair, and DNA Methylation |journal=PLOS Genetics |date=6 July 2007 |volume=3 |issue=7 |pages=e110 |doi=10.1371/journal.pgen.0030110 |pmid=17616978 |pmc=1913100 |doi-access=free |quote=...data support a mechanistic link between HR and DNA methylation and suggest that DNA methylation in eukaryotes marks homologous recombined segments.}}</ref> Such mutations and epigenetic alterations can give rise to [[cancer]] (see [[Neoplasm#Malignant neoplasms|malignant neoplasms]]).<ref name="O'Hagan2008" /><ref name="Cuozzo2007" />{{Verify source<!-- Both references supplied talked about the silencing of the genes that were repaired, but the references seem highly technical, someone please check. Clarification also would be appreciated. [Note from 2nd editor in July 2022: added quotes to cites, but changed statement from "is likely central to progression to cancer" as that is too strong going by sources used.]-->| date = June 2020 }} Investigation of epigenetic down- or upregulation of repaired DNA genes as possibly central to progression of cancer has been regularly undertaken since 2000.<ref>{{cite journal |last1=Baxter |first1=Eva |last2=Windloch |first2=Karolina |last3=Gannon |first3=Frank |last4=Lee |first4=Jason S |title=Epigenetic regulation in cancer progression |journal=Cell & Bioscience |date=December 2014 |volume=4 |issue=1 |pages=45 |doi=10.1186/2045-3701-4-45|pmid=25949794 |pmc=4422217 |doi-access=free }}</ref>

Epigenetic downregulation of the DNA repair gene ''[[O-6-methylguanine-DNA methyltransferase|MGMT]]'' occurs in 93% of bladder cancers,<ref>{{cite journal |last1=Bilgrami |first1=Shumaila M |last2=Qureshi |first2=Sohail A |last3=Pervez |first3=Shahid |last4=Abbas |first4=Farhat |title=Promoter hypermethylation of tumor suppressor genes correlates with tumor grade and invasiveness in patients with urothelial bladder cancer |journal=SpringerPlus |date=December 2014 |volume=3 |issue=1 |pages=178 |doi=10.1186/2193-1801-3-178|pmid=24790823 |pmc=4000596 |doi-access=free }}</ref> 88% of stomach cancers, 74% of thyroid cancers, 40&ndash;90% of colorectal cancers, and 50% of brain cancers.{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}} Similarly, epigenetic downregulation of ''[[LIG4]]'' occurs in 82% of colorectal cancers and epigenetic downregulation of ''[[NEIL1]]'' occurs in 62% of [[head and neck cancer]]s and in 42% of [[non-small-cell lung carcinoma|non-small-cell lung cancer]]s.

Epigenetic upregulation of the DNA repair genes ''[[PARP1]]'' and ''[[FEN1]]'' occurs in numerous cancers (see [[Regulation of transcription in cancer]]). ''PARP1'' and ''FEN1'' are essential genes in the error-prone and mutagenic DNA repair pathway [[microhomology-mediated end joining]]. If this pathway is upregulated, the excess mutations it causes can lead to cancer. [[PARP1]] is over-expressed in tyrosine kinase-activated leukemias,<ref>{{cite journal |last1=Muvarak |first1=Nidal |last2=Kelley |first2=Shannon |last3=Robert |first3=Carine |last4=Baer |first4=Maria R. |last5=Perrotti |first5=Danilo |last6=Gambacorti-Passerini |first6=Carlo |last7=Civin |first7=Curt |last8=Scheibner |first8=Kara |last9=Rassool |first9=Feyruz V. |title=c-MYC Generates Repair Errors via Increased Transcription of Alternative-NHEJ Factors, LIG3 and PARP1, in Tyrosine Kinase–Activated Leukemias |journal=Molecular Cancer Research |date=1 April 2015 |volume=13 |issue=4 |pages=699–712 |doi=10.1158/1541-7786.MCR-14-0422|pmid=25828893 |pmc=4398615 }}</ref> in neuroblastoma,<ref>{{cite journal |last1=Newman |first1=Erika A. |last2=Lu |first2=Fujia |last3=Bashllari |first3=Daniela |last4=Wang |first4=Li |last5=Opipari |first5=Anthony W. |last6=Castle |first6=Valerie P. |title=Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma |journal=Molecular Cancer Research |date=1 March 2015 |volume=13 |issue=3 |pages=470–482 |doi=10.1158/1541-7786.MCR-14-0337|pmid=25563294 |s2cid=1830505 |url=https://figshare.com/articles/journal_contribution/22517004 }}</ref> in testicular and other germ cell tumors,<ref>{{cite journal |last1=Mego |first1=Michal |last2=Cierna |first2=Zuzana |last3=Svetlovska |first3=Daniela |last4=Macak |first4=Dusan |last5=Machalekova |first5=Katarina |last6=Miskovska |first6=Viera |last7=Chovanec |first7=Michal |last8=Usakova |first8=Vanda |last9=Obertova |first9=Jana |last10=Babal |first10=Pavel |last11=Mardiak |first11=Jozef |title=PARP expression in germ cell tumours |journal=Journal of Clinical Pathology |date=July 2013 |volume=66 |issue=7 |pages=607–612 |doi=10.1136/jclinpath-2012-201088|pmid=23486608 |s2cid=535704 }}</ref> and in Ewing's sarcoma.<ref>{{cite journal |last1=Newman |first1=Robert |last2=Soldatenkov |first2=Viatcheslav |last3=Dritschilo |first3=Anatoly |last4=Notario |first4=Vicente |title=Poly(ADP-ribose) polymerase turnover alterations do not contribute to PARP overexpression in Ewing's sarcoma cells |journal=Oncology Reports |date=1 May 2002 |volume=9 |issue=3 |pages=529–532 |doi=10.3892/or.9.3.529|pmid=11956622 }}</ref> [[FEN1]] is upregulated in the majority of cancers of the breast, prostate, stomach, neuroblastomas, pancreas, and lung.<ref>{{cite journal |last1=Xu |first1=H |last2=Zheng |first2=L |last3=Dai |first3=H |last4=Zhou |first4=M |last5=Hua |first5=Y |last6=Shen |first6=B |title=Chemical-induced cancer incidence and underlying mechanisms in Fen1 mutant mice. |journal=Oncogene |date=2011 |volume=30 |issue=9 |pages=1072–1081|doi=10.1038/onc.2010.482 |pmid=20972458 |pmc=3832200 }}</ref> {{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}}