HomeENGLISH MAGAZINEHistone scan by Bard1 to flawlessy repair the damage done

Histone scan by Bard1 to flawlessy repair the damage done

Cancer research often involves a multipronged approach. Of course, testing new treatments and finding novel ways to attack tumors is paramount. At the same time, it is also vital to understand the mechanisms that lead to cancer in the first place. It is only by picking apart the complexity of cancer that we can learn how to overcome it once and for all. When a cell divides, the DNA within it also divides and replicates. Sometimes, that replication is imperfect and produces a mutation. Mutations can also occur during normal metabolic processes ordue to external factors, such as environmental chemicals (urban pollution itself), cigarette smoking or exposure to ultraviolet light. In time, mutations can build up. In some cells, this causes irreversible aging or senescence. In other cells, it ends in programmed cell death (apoptosis). Others still will lose their ability to understand instructions and grow out of control, eventually forming a cancerous tumor. After around six mutations, a cell can become cancerous. Because DNA damage is a natural part of life, cells have developed molecular systems to repair it. A group of researchers from the University of Copenhagen in Denmark is particularly interested in the mechanisms behind DNA repair.

The researchers recently studied one of the primary mechanisms and published their findings in the journal Nature Cell Biology. Cells have two primary repair systems — one of which is much more effective than the other. The best-performing repair system uses a process called homologous recombination. The authors describe it as the flawless system. This system creates a perfect 3D replacement of the damaged DNA, whereas the less accurate method simply “glues” DNA strings together in a more haphazard way, leaving room for errors. In its efforts to understand how a cell decides which of the two mechanisms to use, the team identified a “scanner” within cells. This scanner decides whether or not to activate flawless DNA repair. Once triggered, this cellular pathway fixes mutations that could otherwise lead to cancer. Understanding how the body promotes this process would be useful for scientists looking to prevent the onset of cancer. Lead researcher Prof. Anja Groth explained: “We have discovered how the cell launches the flawless system for serious DNA damage repair and thus protects against cancer. This is done using a protein you could call a ‘molecular scanner,’ which scans the histones in the cell and on that basis launches the repair process”.

Histones are proteins that help package DNA; they also play a part in regulating gene expression. When the researchers examined the two DNA repair processes, they found that the less effective DNA repair method was much easier to trigger, so the body used it more often. Researchers are aware of many cellular “tumor suppressors” genes, one of which is BARD1. Tumor suppressors are genes that interrupt one of the steps between healthy cells and cancerous cells, reducing cancer risk. In this study, the team showed that BARD1 acts as the scanner outlined above. This is the first time that scientists have observed BARD1 working in this way. Most, if not all, BRCA1 (breast cancer 1 protein oncogene) heterodimerizes with BARD1 in vivo. The BARD1/BRCA1 interaction is disrupted by tumorigenic aminoacid substitutions in BRCA1, implying that the formation of a stable complex between these proteins may be an essential aspect of BRCA1 tumor suppression. BARD1 may be the target of oncogenic mutations in breast or ovarian cancer. Mutations in the BARD1 protein appear in many breast, ovarian and uterine cancers, suggesting the mutations disable BARD1 tumor suppressor function.

The authors say that BARD1 sets off a cascade of messengers that switches the flawless DNA repair system into gear, thereby fixing mutations and ultimately reducing cancer risk. When a cell is preparing to split into two, for a short while, it carries two identical DNA strings. BARD1 detects when a cell is in this phase and, if it is, blocks the less efficient DNA repair system. Flawless repair kicks in and uses the duplicate strand to fix the chromatin flawlessly. Following on from these findings, the researchers hope to find ways of influencing these repair mechanisms to create new and improved cancer treatments.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Nakamura M et al. Nat Cell Biol. 2019 Mar; 21(3):311-318.

Padeken J et al., Gasser SM. Genes Dev. 2019 Feb 25.

Yoshino Y et al., Chiba N. Sci Rep. 2019 Feb 7; 9(1):1644. 

Li Q, Saito TT et al. PLoS Genet. 2018; 14(11):e1007701. 

Dott. Gianfrancesco Cormaci
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (leader of the R&D for the partnership CoFood s.r.l.) - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica e salute sui siti web salutesicilia.com, medicomunicare.it e in lingua inglese sul sito www.medicomunicare.com
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