Research team identifies new mechanism for protecting DNA
Discovery offers hope to better understand how diseases like cancer,
premature aging can be prevented

Date:
January 18, 2022
Source:
Case Western Reserve University
Summary:
Researchers have identified a new mechanism by which a protein
known for repairing damaged DNA also protects the integrity of
DNA by preserving its structural shape. The discovery, involving
the protein 53BP1, offers insight into understanding how cells
maintain the integrity of DNA in the nucleus, which is critical
for preventing diseases like premature aging and cancer.



FULL STORY ========================================================================== Researchers from Case Western Reserve University have identified a
new mechanism by which a protein known for repairing damaged DNA also
protects the integrity of DNA by preserving its structural shape.


==========================================================================
The discovery, involving the protein 53BP1, offers insight into
understanding how cells maintain the integrity of DNA in the nucleus,
which is critical for preventing diseases like premature aging and cancer.

A research team led by Youwei Zhang, an associate professor of
pharmacology at the Case Western Reserve School of Medicine and a member
of the Molecular Oncology Program at the Case Comprehensive Cancer Center, conducted the study.

The findings were published (Jan. 18, 2022) in Nature Communications.

DNA, or deoxyribonucleic acid, is the chemical name for the molecule
that carries genetic instructions in all living things.

53BP1 is a large protein known for determining how cells will repair a particular type of DNA damage -- DNA double-strand break (DSB), in which
the two strands of DNA are both broken, leaving a free DNA end floating
around in the cell's nucleus.

When DSB occurs, if not repaired, DNA ends could fuse to what it should
not under normal conditions, which leads to the disruption of genetic information.

In the short term, cells with unrepaired DNA may kill themselves off;
but if a cell lost this self-surveillance, it may start the journey
toward cancer.



==========================================================================
The study In this study, the team discovered 53BP1 has a biological
function in mediating the structure of DNA, specifically at a highly
compacted region called heterochromatin.

The researchers found that this new function involves a new form of
activity of 53BP1, in which the protein accumulates at the condensed DNA regions and forms small liquid droplets -- a process called liquid-liquid
phase separation, similar to mixing oil with water for salad dressing.

The team determined how 53BP1 can form liquid droplets: They found
that this process requires the participation of other proteins known
to support the structure of those highly condensed DNA. But, in turn,
they discovered that 53BP1 actually stabilized the gathering of these
proteins at these DNA regions, which is important for keeping the overall function of the DNA.

They then carried out detailed molecular analysis to break the large
protein into small pieces and determined which pieces are important for
the liquid droplet formation of 53BP1. They further changed amino acid of
a specific position of the 53BP1 protein and determined the contribution
of several amino acids that are critical for this new function.

"More excitingly, through these comprehensive analyses, we found that
this new protective activity of 53BP1 is independent of the widely known
role of this protein in repairing DNA damage, indicating a totally new
function of 53BP1," Zhang said. "Our study suggests that, in addition
to DSB repair modulation, 53BP1 contributes to the maintenance of genome stability through the formation of these liquid droplets." With this new information, Zhang and his team hope to better understand how diseases
like cancer can be prevented, and even design therapies that use this
new feature of 53BP1 to treat cancers in the future.

Zhang's lab focuses on understanding cell biology to develop anticancer therapies -- specifically how cells protect the stability of DNA. Without
that protection, it can cause genome instability and eventually lead
to the early onset of degenerative disorders such as premature aging
and cancer.

"Our goal," Zhang said, "is to understand the molecular mechanisms
that maintain the genome stability in human cells by identifying
the genes and the signaling pathways involved. Long term, we hope to
translate this knowledge into potential anticancer treatment strategies." ========================================================================== Story Source: Materials provided by Case_Western_Reserve_University. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Lei Zhang, Xinran Geng, Fangfang Wang, Jinshan Tang, Yu Ichida,
Arishya
Sharma, Sora Jin, Mingyue Chen, Mingliang Tang, Franklin Mayca
Pozo, Wenxiu Wang, Janet Wang, Michal Wozniak, Xiaoxia Guo, Masaru
Miyagi, Fulai Jin, Yongjie Xu, Xinsheng Yao, Youwei Zhang. 53BP1
regulates heterochromatin through liquid phase separation. Nature
Communications, 2022; 13 (1) DOI: 10.1038/s41467-022-28019-y ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220118154842.htm

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