Overview human DNA Repair Genes, their Mechanisms and Treatment

Overview of human DNA Repair Genes, their Mechanisms, and Treatment

by

*Robert Gorter, MD, PhD.

*Emeritus Professor, University of Calfornia San Francisco Medical School (UCSF)

*Associate Professor University Witten-Herdecke, etc.

May 26th, 2022

DNA

DNA Repair Mechanisms and Pathways in Cancer Therapy and Resistance

Ronen A, Glickman BW. Human DNA repair genes. Environ Mol Mutagen. 2001;37(3):241-83. DOI: 10.1002/em.1033. PMID: 11317342.

Also, when one does not smoke or drink alcohol on a daily basis and restricts glucose intake, still on average, an adult human being produces approximately 100,000 cancer cells per day. These cancer cells occur during replication (mitosis) of a cell, which must produce two identical cells but mistakes in the copying process occur by, for instance, a wrong aminoacid is built in. A human cell contains 46 chromosomes; each chromosome contains tens of thousands of genes; each gene contains millions of DNA molecules. When necessary, one cell can divide into two cells within 24 hours. There, mistakes can be made in copying all DNA molecules and thus, in all genes and chromosomes. Each mistake becomes a mutation.  Mutations cause an array of illnesses, including cancer. Therefore, it most essential that if a mutation by a mistake in the copying process took place, this mistake is instantly noticed and repaired.

Thus, DNA repair mechanisms are essential for the maintenance of genome integrity. Consequently, the dysregulation of repair genes can be expected to be associated with significant, detrimental health effects, which can include an increased prevalence of birth defects, an enhancement of cancer risk, and an accelerated rate of aging. Although original insights into DNA repair and the genes responsible were largely derived from studies in bacteria and yeast, well over 125 genes directly involved in DNA repair have now been identified in humans, and their cDNA sequence established. These genes function in a diverse set of pathways that involve the recognition and removal of DNA lesions, tolerance to DNA damage, and protection from errors of incorporation made during DNA replication or DNA repair. Additional genes indirectly affect DNA repair, by regulating the cell cycle, ostensibly to provide an opportunity for repair or to direct the cell to apoptosis.

About 70 of the DNA repair genes have been identified: both the genomic DNA sequence and the cDNA sequence and chromosomal location have been elucidated. In 45 cases, single-nucleotide polymorphisms have been identified and, in some cases, genetic variants have been associated with specific disorders. With the accelerating rate of gene discovery, the number of identified DNA repair genes and sequence variants is quickly rising.

Mistletoe (Viscum album) has been shown to dramatically improve DNA repair, leading to a significant prolongation of Life Expectancy and Qualify of Life (see list of refered articles).

Mistletoe (Viscum album) in cancer therapy

Patients receiving chemotherapy and/or radiation will always have significant inhibition or even destruction of their DNA repair mechanisms. Usually, chemotherapy and all forms of ionizing radiation will cause cancer by themselves. Therefore, also studies with Viscum album document a significant improvement in life expectancy and quality of life during and after treatment with Viscum album.

In the Gorter Model, treatment with the Viscum album is one of its cornerstones. In Europe and many other countries, Viscum album is available on prescription and often reimbursed by the health insurance systems

 

Sources

Coding variants in human double-strand break DNA repair genes.

Ruttan CC, Glickman BW. Mutat Res. 2002 Nov 30;509(1-2):175-200. DOI: 10.1016/s0027-5107(02)00218-x. PMID: 12427538

Human DNA repair genes, 2005.

Wood RD, Mitchell M, Lindahl T. Mutat Res. 2005 Sep 4;577(1-2):275-83. DOI: 10.1016/j.mrfmmm.2005.03.007. PMID: 15922366 Review.

Human DNA repair systems: an overview.

Yu Z, Chen J, Ford BN, Brackley ME, Glickman BW. Environ Mol Mutagen. 1999;33(1):3-20. doi: 10.1002/(sici)1098-2280(1999)33:1<3::aid-em2>3.0.co;2-l. PMID: 10037319 Review.

Human cells are deficient in p53-regulated p21(waf1/cip1) expression exhibit normal nucleotide excision repair of UV-induced DNA damage.

Wani MA, Wani G, Yao J, Zhu Q, Wani AA. Carcinogenesis. 2002 Mar;23(3):403-10. doi: 10.1093/Marcin/23.3.403. PMID: 11895854

The barley EST DNA Replication and Repair Database (bEST-DRRD) as a tool for the identification of the genes involved in DNA replication and repair.

Gruszka D, Marzec M, Szarejko I. BMC Plant Biol. 2012 Jun 14;12:88. doi: 10.1186/1471-2229-12-88. PMID: 22697361 Free PMC article.

Germline Mutations in DNA Repair Genes in Patients With Metastatic Castration-resistant Prostate Cancer.

Holeckova K, Baluchova K, Hives M, Musak L, Kliment J Sr, Skerenova M.

In Vivo. 2020 Jul-Aug;34(4):1773-1778. doi: 10.21873/invivo.11971. PMID: 32606146 Free PMC article.

DNA damage accumulates and responses are engaged in human ALS brain and spinal motor neurons and DNA repair is activatable in iPSC-derived motor neurons with SOD1 mutations.

Kim BW, Jeong YE, Wong M, Martin LJ. Acta Neuropathol Commun. 2020 Jan 31;8(1):7. doi: 10.1186/s40478-019-0874-4. PMID: 32005289 Free PMC article.

Low-Level Radiofrequency Exposure Does Not Induce Changes in MSC Biology: An in vitro Study for the Prevention of NIR-Related Damage.

Alessio N, Santoro E, Squillaro T, Aprile D, Briccola M, Giubbini P, Marchesani R, Muoio MR, Lamberti M. Stem Cells Cloning. 2019 Dec 18;12:49-59. doi: 10.2147/SCCAA.S204166. eCollection 2019. PMID: 31908499 Free PMC article.

DNA Repair Gene Expression Adjusted by the PCNA Metagene Predicts Survival in Multiple Cancers.

Peterson LE, Kovyrshina T. Cancers (Basel). 2019 Apr 8;11(4):501. doi: 10.3390/cancers11040501. PMID: 30965671 Free PMC article.

Stress and stem cells: adult Muse cells tolerate extensive genotoxic stimuli better than mesenchymal stromal cells.

Alessio N, Squillaro T, Özcan S, Di Bernardo G, Venditti M, Melone M, Peluso G, Galderisi U. Oncotarget. 2018 Apr 10;9(27):19328-19341. doi: 10.18632 / oncotarget.25039. eCollection 2018 Apr 10. PMID: 29721206 Free PMC article.

Improvement of DNA repair in lymphocytes of breast cancer patients treated with Viscum album extract (Iscador)

Kovacs E, Hajto T, Hostanska K. Improvement of DNA repair in lymphocytes of breast cancer patients treated with Viscum album extract (Iscador). Eur J Cancer. 1991;27(12):1672-6. doi: 10.1016/0277-5379(91)90443-h. PMID: 1782081.

E Kovacs, T Hajto, K Hostanska

Articles in Regard to the Clinical Application of Viscum album

Unconventional therapies for cancer: 3. Iscador. Task Force on Alternative Therapies of the Canadian Breast Cancer Research Initiative.

Kaegi E. CMAJ. 1998 May 5;158(9):1157-9. PMID: 9597967 Free PMC article.

Use of Iscador, an extract of European mistletoe (Viscum album), in cancer treatment: prospective nonrandomized and randomized matched-pair studies nested within a cohort study.

Grossarth-Maticek R, Kiene H, Baumgartner SM, Ziegler R. Altern Ther Health Med. 2001 May-Jun;7(3):57-66, 68-72, 74-6 passim. PMID: 11347286 Clinical Trial.

Anticarcinogenic and antimetastatic activity of Iscador.

Kuttan G, Menon LG, Antony S, Kuttan R. Anticancer Drugs. 1997 Apr;8 Suppl 1:S15-6. doi: 10.1097/00001813-199704001-00004. PMID: 9179361

Randomised and non-randomised prospective controlled cohort studies in matched-pair design for the long-term therapy of breast cancer patients with a mistletoe preparation (Iscador): a re-analysis.

Grossarth-Maticek R, Ziegler R. Eur J Med Res. 2006 Nov 30;11(11):485-95.

PMID: 17182361 Clinical Trial.

Immune modulation using mistletoe (Viscum album L.) extracts Iscador.

Büssing A. Arzneimittelforschung. 2006 Jun;56(6A):508-15. doi: 10.1055/s-0031-1296818. PMID: 16927532 Review.

Efficacy of mistletoe extract as a complement to standard treatment in advanced pancreatic cancer: study protocol for a multicentre, parallel group, double-blind, randomised, placebo-controlled clinical trial (MISTRAL).

Wode K, Hök Nordberg J, Kienle GS, Elander NO, Bernhardson BM, Sunde B, Sharp L, Henriksson R, Fransson P. Trials. 2020 Sep 11;21(1):783. doi:10.1186 / s13063-020-04581-y. PMID: 32917288 Free PMC article.

Clinical Safety of Combined Targeted and Viscum album L. Therapy in Oncological Patients.

Thronicke A, Oei SL, Merkle A, Matthes H, Schad F. Medicines (Basel). 2018 Sep 6;5(3):100. doi: 10.3390/medicines5030100. PMID: 30200590 Free PMC article.

Evaluation of Preclinical Assays to Investigate an Anthroposophic Pharmaceutical Process Applied to Mistletoe (Viscum album L.) Extracts.

Baumgartner S, Flückiger H, Kunz M, Scherr C, Urech K. Evid Based Complement Alternat Med. 2014;2014:620974. doi: 10.1155/2014/620974. Epub 2014 May 4. PMID: 24876872 Free PMC article.

Oncopharmacological Perspectives of a Plant Lectin (Viscum album Agglutinin-I): Overview of Recent Results from in vitro Experiments and in vivo Animal Models, and Their Possible Relevance for Clinical Applications.

Hajtó T, Hostanska K, Berki T, Pálinkás L, Boldizsár F, Németh P. Evid Based Complement Alternat Med. 2005 Mar;2(1):59-67. doi: 10.1093/ecam/neh058. Epub 2005 Jan 28. PMID: 15841279 Free PMC article.

Unconventional therapies for cancer: 3. Iscador. Task Force on Alternative Therapies of the Canadian Breast Cancer Research Initiative.

Kaegi E. CMAJ. 1998 May 5;158(9):1157-9. PMID: 9597967 Free PMC article.

 

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