DNA repair cleanup failure – a root cause for cancers?

New research suggests that the answer to the question is quite possibly.  This is a rather technial subject and I will get into it in stages.  Finally, I speculate a little on the possible importance of the new research.

Repair mechanisims for double-strand breaks in DNA

In the course of a normal good day you may have a million or more events of DNA damage occur in your body.  If you are exposed to ionizing radiation or any substance that creates large numbers of free radicals or if you have certain disease processes like Alzheimer’s going on, the number of DNA damage events could be many times higher.  The kinds of DNA damage can be of multiple types(ref).  In this blog entry I am concerned with one particular important kind, double-strand breaks (DSBs), breaks that can occur naturally in cell differentiation or that are created by radiation and certain chemicals.   “The current view is that most spontaneous chromosomal rearrangements result from DSBs created mainly during DNA replication as a result of broken, stalled or collapsed replication forks(ref).”  

Because these breaks completely threaten genomic integrity, evolution has provided us with a number of sophisticated approaches for automatic DNA repair.  See Dancing on damaged chromatin: functions of ATM and the RAD50/MRE11/NBS1 complex in cellular responses to DNA damage.  In order to preserve and protect genetic information, eukaryotic cells have developed a signaling or communications network to help the cell respond to DNA damage, and ATM and NBS1 are key players in this network. ATM is a protein kinase which is activated immediately after a DNA double strand break (DSB) is formed, and the resulting signal cascade generated in response to cellular DSBs is regulated by post-translational protein modifications such as phosphorylation and acetylation. In addition, to ensure the efficient functioning of DNA repair and cell cycle checkpoints, the highly ordered structure of eukaryotic chromatin must be appropriately altered to permit access of repair-related factors to DNA. These alterations are termed chromatin remodeling.”

Failure to repair double-strand DNA breaks or faulty repairs can have serious consequences.  As pointed out in the review publication Misrepair of radiation-induced DNA double-strand breaks and its relevance for tumorigenesis and cancer treatment:  “The faithful repair of DNA double-strand breaks (DSBs) is probably one of the most critical tasks for a cell in order to maintain its genomic integrity since these lesions may lead to chromosome breaks or rearrangements, mutations, cell death or cancer. DSBs can arise spontaneously during normal cellular DNA metabolism or may be induced by exogenous agents such as ionizing radiation. To overcome the danger that emanates from these lesions, eukaryotic cells have evolved specific pathways for processing DSBs. —    Moreover, it is thought that an impaired capacity to repair double-strand breaks can lead to chromosome Instability (CIN) “ — a genome phenotype that involves changes in chromosome number or structure, and accounts for most malignancies(ref).”

There are two general repair pathways for double strand breaks, homologous recombination (HR) and non-homologous end joining (NHEJ). “Defects in either repair pathway result in high frequencies of genomic instability[4]. The HR pathway utilizes a homologous sequence to faithfully restore the DNA continuity at the DSB[5]. In contrast, NHEJ is a mechanism able to join DNA ends with no or minimal homology [6] (ref).”  “Non-homologous DNA end-joining (NHEJ)–the main pathway for repairing double-stranded DNA breaks–functions throughout the cell cycle to repair such lesions. Defects in NHEJ result in marked sensitivity to ionizing radiation and ablation of lymphocytes, which rely on NHEJ to complete the rearrangement of antigen-receptor genes. NHEJ is typically imprecise, a characteristic that is useful for immune diversification in lymphocytes, but which might also contribute to some of the genetic changes that underlie cancer and ageing(ref).”

The DNA repair pathways are complex but one gene/protein important both to faithful cell division and DNA repair appears to be Mms22, studied originally in budding yeast strains(ref)(ref). 

Roles of proteasomes in repairing double-strand DNA breaks

I found the new February 2010 publication Proteasome Nuclear Activity Affects Chromosome Stability by Controlling the Turnover of Mms22, a Protein Important for DNA Repair to be difficult to decipher at first.  So, I need to proceed slowly here.   Proteasomes are tiny protein recycling factories that live in cells, either in the cytoplasm or in the nucleus.  Actually they are sizeable protein complexes shaped like drums that breakup unneeded proteins (ones that are damaged, misfolded or used for short-term purposes as part of cell maintenance) using a chemical process called proteolysis.  “The degradation process yields peptides of about seven to eight amino acids long, which can then be further degraded into amino acids and used in synthesizing new proteins.[2] Proteins are tagged for degradation with a considerably small protein called ubiquitin.  — The proteasomal degradation pathway is essential for many cellular processes, including the cell cycle, the regulation of gene expression, and responses to oxidative stress(ref).” 

For a long time is was thought that  DNA duplication and repair had nothing to do with the proteasomes, nothing anymore than an effective pressure cooker has to do with a garbage dispose-all.  The new research says “not so.”  In fact, DNA repair might not be completed because of defects in proteasome machinery. 

The new publication cites impressive research indicating that what goes on when a double-strand DNA break occurs includes 1.  Mms22 gets attracted to the double break site where it does its repair job.  2.  In the process Mms22 also gets highly ubiquinated, e.g. several morsels of ubiquitin are attached to it and thus it becomes a target for proteasomal degradation, 3.  Certain proteasomes (“The 26S proteasome comprises the 20S core particle (CP) and the 19S regulatory particle (RP), which represent the base and lid substructures, respectively(ref).”) are also attracted to the DNA break site, probably by accumulated ubiquinated Mms22, where they capture and set out to degrade the Mms22.  4.  If degradation is successful the DNA repair is completed, and 5.  If degradation is not successful the DNA break repair is not completed and the cell goes into prolonged cell-cycle arrest. 

“Indeed, we show that DNA damage results in Mms22 recruitment to the chromatin bound fraction –. Importantly, our results also show that recruitment of Mms22 to chromatin is not sufficient for the normal course of DNA repair, and that an essential step is a proteasome-mediated degradation of Mms22. These results thus identify for the first time a proteasome target that links proteasomal nuclear activity and DNA double strand break repair(ref).”  Also, “In this regard, proteasome inhibition in combination with DNA damage probably results in the accumulation of many proteins besides Mms22, which altogether may lead to the impaired recovery from the cell cycle arrest(ref).”The authors of the paper put it this way: “DNA damage results in a SCFrtt101 E3 ubiquitin ligase-dependent accumulation of the ubiquitinated form of Mms22 on chromatin that, as suggested above, plays a role in dealing with DNA damage. Subsequent degradation of ubiquitinated Mms22 by the proteasome is an important step in completion of the DNA repair process. Once Mms22 executes its function in DNA repair it becomes a target for degradation by the UPS (ubiquitin proteasome system), and is removed from chromatin.  Failure to degrade Mms22 results in impaired DNA repair and prolonged cell cycle arrest(ref).”

The authors point the finger for failure in double strand repair (and consequently for chromosome instability and carcinogenesis) to defects in the proteasomes: “In our current work, we show that mutations in the proteasome subunits rpn5ΔC and pup2, which cause nuclear mislocalization, are associated with impaired DSB (double-strand break) repair. All other proteasomal Ts mutants tested were sensitive to drugs inducing DSBs, implying that the proteolytic activity of the proteasome is required for DNA repair(ref).”  As mentioned, the mutations can cause the proteasomes of concern to locate outside of the cell nucleus where they normally reside making them unavailable to ubiquinated Mms22.

The research work described was done using strains of yeast (Saccharomyces cerevisiae) but is thought to be applicable to humans because of orthologs between human and yeast genes(ref)(ref).   

What I take away from this research is:

·        What we have here is another case of what was thought to be a well-understood cell component (a proteasome) showing up with a brand new function and importance. 

 ·        It provides another chunk of understand about important cell processes, another piece of the giant jigsaw puzzle that will eventually make clear to us what aging is and what we can do about it.  See my blog post The longevity jigsaw puzzle.

·        With each new piece of the puzzle, it seems that more questions are raised than are answered.  In the case of the research described above some of the questions are: Do these results largely based on yeast studies completely carry over to apply to humans?   If so, what can be done about defects in the genes for the proteasome subunits rpn5ΔC and pup2 to help prevent cancers?  Do proteasomes play a similar role with other DNA repair genes besides Mms22? What other interventions might be suggested by this work to improve efficiency of repair of double-strand DNA breaks?

·        There is a lot more interesting research related to DNA repair beyond the thread covered here and I will probably come back to that topic again before too long. 

About Vince Giuliano

Being a follower, connoisseur, and interpreter of longevity research is my latest career. I have been at this part-time for well over a decade, and in 2007 this became my mainline activity. In earlier reincarnations of my career. I was founding dean of a graduate school and a university professor at the State University of New York, a senior consultant working in a variety of fields at Arthur D. Little, Inc., Chief Scientist and C00 of Mirror Systems, a software company, and an international Internet consultant. I got off the ground with one of the earliest PhD's from Harvard in a field later to become known as computer science. Because there was no academic field of computer science at the time, to get through I had to qualify myself in hard sciences, so my studies focused heavily on quantum physics. In various ways I contributed to the Computer Revolution starting in the 1950s and the Internet Revolution starting in the late 1980s. I am now engaged in doing the same for The Longevity Revolution. I have published something like 200 books and papers as well as over 430 substantive.entries in this blog, and have enjoyed various periods of notoriety. If you do a Google search on Vincent E. Giuliano, most if not all of the entries on the first few pages that come up will be ones relating to me. I have a general writings site at www.vincegiuliano.com and an extensive site of my art at www.giulianoart.com. Please note that I have recently changed my mailbox to vegiuliano@agingsciences.com.
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  1. Pingback: Genomic stability, DNA repair and the sirtuin SIRT6 | AGING SCIENCES – Anti-Aging Firewalls

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