[GRG] Protease Removes DNA-Protein Crosslinks, Restores Replication


Jul 9, 2014

Protease Removes DNA-Protein Crosslinks, Restores Replication

Protease Removes DNA-Protein Crosslinks, Restores Replication
Formaldehyde can crosslink DNA to proteins, which interferes with
DNA replication. The repair protein Wss1 chops down the protein
component of DNA-protein crosslinks, thereby restoring replication.
[MPI of Biochemistry/S. Jentsch]

The cellular machinery that replicates DNA would soon stall were it
poorly maintained. It is vulnerable to gunky buildup—lesions from
various endogenous and exogenous sources. Some gunk removal
mechanisms are fairly well known. For example, nucleotide excision
repair and homologous recombination have been well studied. Less
familiar, however, are repair mechanisms that specifically target
the protein component of DNA-protein crosslinks (DPCs).

Reactive compounds such as formaldehyde, which are produced as
byproducts of cellular reactions, cause the crosslinking of
proteins to DNA. Importantly, DPCs are also caused by several
anticancer drugs and are extremely toxic as they interfere with
essential processes such as DNA replication. Cells need to unwind
and separate the DNA double helix in order to copy its genetic
information prior to the next round of cell division. DPCs inhibit
this process by blocking the way of the unwinding enzyme
replicative helicase, thus preventing replication and consequently
cell division.

In the laboratory of Prof. Stefan Jentsch, Ph.D., at the Max-Planck-
Institute of Biochemistry, scientists have identified the protease
Wss1 as a new safeguarding factor that cleaves the protein
components of DPCs and thereby enables cells to duplicate their
genome. Details of this work appeared July 3 in the journal Cell,
in an article entitled, “A DNA-Dependent Protease Involved in DNA-
Protein Crosslink Repair.”

In this article, the authors describe how they determined that the
metalloprotease Wss1 is crucial for cell survival upon exposure to
formaldehyde and topoisomerase 1-dependent DNA damage. “Yeast
mutants lacking Wss1 accumulate DPCs and exhibit gross chromosomal
rearrangements,” they wrote. “Notably, in vitro assays indicate
that substrates such as topoisomerase 1 are processed by the
metalloprotease directly and in a DNA-dependent manner.”

In other words, Wss1 has the unique property of cleaving proteins
only in the presence of DNA, suggesting that the enzyme is well
tailored for its task to remove crosslinks from the genome and thus
preserve genome stability. By clearing away DPCs, the Wss1 protease
may, the authors speculate, enable the “repair of these unique
lesions via downstream canonical DNA repair pathways.”

Because the repair of DNA lesions is essential to prevent cancer
formation, it is of crucial importance to understand the underlying
cellular mechanisms. The newly identified DNA-protein crosslink-
repair pathway is particularly important for rapidly dividing
cells. Given the fact that cancer cells divide much faster than the
majority of human cells, Wss1 might be an attractive future drug
target for cancer therapy.


About Johnny Adams

My full-time commitment is to slow and ultimately reverse age related functional decline to increase healthy years of life. I’ve been active in this area since the 1970s, steadily building skills and accomplishments. I have a good basic understanding of the science of aging, and have many skills that complement those of scientists so they can focus on science to advance our shared mission. Broad experience Top skills: administration, management, information technology (data and programming), communications, writing, marketing, market research and analysis, public speaking, forging ethical win-win outcomes among stakeholders (i.e. high level "selling"). Knowledge in grant writing, fundraising, finance. Like most skilled professionals, I’m best described as a guy who defines an end point, then figures out how to get there. I enjoy the conception, design, execution and successful completion of a grand plan. Executive Director Gerontology Research Group (GRG). Manages Email discussion forum, web site, meetings and oversees supercentenarian (oldest humans, 110+ years) research. CEO / Executive Director Carl I. Bourhenne Medical Research Foundation (Aging Intervention Foundation), an IRS approved 501(c)(3) nonprofit. http://www.AgingIntervention.org Early contributor to Supercentenarian Research Foundation. Co-Founder Geroscience Healthspan Forum. Active contributor to numerous initiatives to increase healthy years of life. Co-authored book on conventional, practical methods available today to slow the processes of aging – nutrition, exercise, behavior modification and motivation, stress reduction, proper supplementation, damage caused by improper programs, risk reduction and others. Fundamental understanding of, and experience in the genomics of longevity (internship analyzing and curating longevity gene papers). Biological and technical includes information technology, software development and computer programming, bioinformatics and protein informatics, online education, training programs, regulatory, clinical trials software, medical devices (CAT scanners and related), hospital electrical equipment testing program. Interpersonal skills – good communication, honest, well liked, works well in teams or alone. Real world experience collaborating in interdisciplinary teams in fast paced organizations. Uses technology to advance our shared mission. Education: MBA 1985 University of Southern California -- Deans List, Albert Quon Community Service Award (for volunteering with the American Longevity Association and helping an elderly lady every other week), George S. May Scholarship, CA State Fellowship. BA psychology, psychobiology emphasis 1983 California State University Fullerton Physiological courses as well as core courses (developmental, abnormal etc). UCLA Psychobiology 1978, one brief but fast moving and fulfilling quarter. Main interest was the electrochemical basis of consciousness. Also seminars at the NeuroPsychiatric Institute. Other: Ongoing conferences, meetings and continuing education. Aging, computer software and information technology. Some molecular biology, biotech, bio and protein informatics, computer aided drug design, clinical medical devices, electronics, HIPAA, fundraising through the Assoc. of Fundraising Professionals. Previous careers include: Marketing Increasing skill set and successes in virtually all phases, with valuable experience in locating people and companies with the greatest need and interest in a product or service, and sitting across the table with decision makers and working out agreements favorable to all. Information Technology: Management, data analysis and programming in commercial and clinical trials systems, and bioinformatics and protein informatics. As IT Director at Newport Beach, CA based technology organization Success Family of Continuing Education Companies, provided online software solutions for insurance and financial professionals in small to Fortune 500 size companies. We were successful with lean team organization (the slower moving competition was unable to create similar software systems). Medical devices: At Omnimedical in Paramount CA developed and managed quality assurance dept. and training depts. for engineers, physicians and technicians. Designed hospital equipment testing program for hospital services division. In my early 20’s I was a musician, and studied psychology and music. Interned with the intention of becoming a music therapist. These experiences helped develop valuable skills used today to advance our shared mission of creating aging solutions.
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