We’ve discovered the secret of life.                                     FRANCIS CRICK

Introduction: Francis Crick’s quote has philosophical meaning as much as scientific one. The secret of life is hidden behind the DNA molecule in our organism, which carries the total information necessary for the cells to develop, and transmit this information from parents to offspring.[1] Initially, DNA (deoxyribonucleic acid) was  isolated in 1869 by Friedrich Miescher in white blood cells of  human pus.[2] Later, in 1953, Francis Crick, and his colleague Watson, revealed the double helix structure of DNA, and published it in the journal Nature, for which they won Nobel prize in 1962 in Stockholm, Sweden.[3]

DNA takes place in many processes of the cell, one of which is replication, the process of the DNA synthesis. It is fast and highly accurate. The high accuracy is based on several proofreading mechanisms that remove errors. One error   is made in every 109 base pair replications. The entire eukaryotic genome is 3×109 base pairs. Most replication mismatches (errors) occur during initiation process and post- replication. Enzymes that repair damaged DNA are DNA-polymerases, glycosylases, ligases, phosphodiesterases, as well as multiple nucleases complexes. But, what does it occur if any of these repair mechanisms is defective? [4]

Latest studies: Failed or defective DNA damage repair system leads to genome chaos. This is a new damage pattern in the genetic material of cancer cells, discovered recently by scientists at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), published in the journal Nature Communications. [5]

They found that in a particularly aggressive children tumor, only a single cellular crisis can cause breaks of sections in individual chromosomes  at innumerable points leading to incorrectly cluster rearrangements, resulting in  the absence of whole parts of chromosome, duplication or incorporation in the wrong direction. The process is known as chromotripsis, which occurs in 20% to 30% of all cancers. It triggers cancer development and affect cancer therapy.[ 6]

Aurelie Ernst and her team  tested the phenomenon on genetically modified mice. The repair process of DNA broken double strands was stopped through switching off the molecules, used  to repair DNA, specifically the neural precursor cells. As a result, these mice developed malignant brain tumors (medulloblastomas and high-grade gliomas), showing chromothripsis at high frequency.                                                                                                                                Furthermore, it was accompanied by overexpression of Myc oncogene. Myc is a proto- oncogene, that when mutated loses the transcriptional control, leading to overexpression of the protein, consequently inducing cell growth, developing cancer. This achievement is proved in humans diagnosed with breast cancer, brain cancer, and melanoma as well.[ 6]

The results show that the chromosomal chaos in the cell nucleus caused by defects in DNA repair systems and overexpression of Myc oncogene increase the frequency of the disease, making it even harder for treatment.[ 7]

Treatment: However, advances in medicine have approached  a new type of therapy for cancer, PARP inhibitors. They are a type of targeted cancer drug. PARP is a protein found in our cells, it stands for poly-ADP ribose polymerase. It helps damaged cells to repair themselves. As a cancer treatment, PARP inhibitors stop the PARP from repairing themselves and the cancer cells die. [8]  FDA has approved the use of olaparib (2014), rucaparib (2016), niraparib (2017) for treating recurrent ovarian cancer.  In the future  treatment with PARP inhibitors could be a new therapeutic option if the genetic analysis of the patients reveals the process of  chromotripsis. This has to be confirmed in pre-clinical and clinical studies. [9]

 

COPYRIGHT: This article is the property of We Speak Science, a non-profit institution co-founded by Dr. Detina Zalli (Harvard University) and Dr. Argita Zalli (Imperial College London). The article is written by Brisilda Pashaj Medical University, Plovdiv, Bulgaria.

REFERENCES:

  1. Lawless Grant D. Reflections: Francis Crick and the Race to Discover the “Secret of Life” P&T, 2004 October; 29 (10): 636-637
  2. Dahm R. Friedrich Miescher and the discovery of DNA. Elsevier, 2005 February; 278(2): 274-288
  3. Nobel lectures, Physiology or Medicine 1942-1962, Elsevier Publishing Company, Amsterdam, 1964
  4. Sarafian V., Vasilevska M, Vatev I, Radeva-Kuyamova X. Medical Biology, Plovdiv 2010, pg39-40
  5. Manasi Ratnaparkhe et al, Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors, Nature Communications(2018). DOI: 10.1038/s41467-018-06925
  6. Stephans et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell2011 Jan 7;144(1):27-40. doi: 10.1016/j.cell.2010.11.055.
  7. Nilsson A. J., Cleveland L. J. Myc pathways provoking cell suicide and cancer Oncogene 2003 December;22: 9007–9021
  8. Davar,1Beumer J.H.,  Hamieh L. Tawbi H. Role of PARP Inhibitors in Cancer Biology and Therapy. Curr Med Chem. 2012 Aug 1; 19(23): 3907–3921.
  9. Bitler Benjamin., Watson L. Zachary., Wheelera J. Lindsay, Behbakhta Kian. PARP inhibitors: Clinical utility and possibilities of overcoming resistance. Gynecologic Oncology 2017 December; 147(3): 695-704