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Werner syndrome RECQ helicase and heterochromatin maintenance in human cells

“Our study highlights WRN as a contributor to the integrity of CH and points at the altered levels and distribution of LBR as a mediating mechanism.”

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Impact Journals LLC

Werner syndrome RECQ helicase participates in and directs maintenance of the protein complexes of constitutive heterochromatin in proliferating human cells

image: 

Figure 1. WRN associates with HDAC2. (A) Representative image of HDAC2/WRN PLA in the isogenic HDAC2+ and hdac2-27 null derivatives of GM639. Scale, 20 µm. (B) Quantitation of HDAC2/WRN PLA performed as in (A). (C) Hdac2-27 cells were stably transfected with HDAC-V5 transgene or empty vector (tag-less) and analyzed by Western blotting with antibodies to NCL (internal control) and V5. (D) Quantitation of IF in situ performed with V5 antibody on the same cells as in (C). MFI, mean fluorescence intensity, a.u., arbitrary units. (E) Representative image of V5/WRN PLA performed on the same cells as in (CD) that were labeled for 30 min with EdU prior to harvest. EdU incorporation was visualized by Clicking to Alexa 488 azide. Scale, 20 µm. (F) Quantitation of V5/WRN PLA performed as in (E). V5/WRN signals of EdU-positive and EdU-negative cells are plotted separately. (G) WI38hTERT cells were stably transfected with the indicated shRNA-expressing constructs and treated with 100 ng/ml doxycycline for 5 days prior to Western blotting with WRN antibody. i.c., internal control (the STING protein). I.c.-normalized WRN levels are shown relative to shNS w/o DOX. (H) Quantitation of HDAC2/WRN PLA performed with the same cells as in (F). Crossbars in jitter plots are distribution means. Here and elsewhere, see Methods for details of p-value calculations.

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Credit: 2024 Lazarchuk et al.

“Our study highlights WRN as a contributor to the integrity of CH and points at the altered levels and distribution of LBR as a mediating mechanism.”

BUFFALO, NY- November 5, 2024 – A new research paper was published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science), Volume 16, Issue 20 on October 17, 2024, entitled, “Werner syndrome RECQ helicase participates in and directs maintenance of the protein complexes of constitutive heterochromatin in proliferating human cells.”

Researchers from the Department of Laboratory Medicine and Pathology at the University of Washington have discovered that the Werner syndrome gene (WRN), linked to premature aging, plays a crucial role in maintaining cellular organization and DNA stability. Their study shows that loss of WRN function disrupts essential protein interactions, potentially accelerating aging as cells lose structural integrity.

Werner syndrome is a rare genetic disorder that causes accelerated aging due to mutations in the WRN gene, which disrupts normal cell functions. The WRN gene is typically responsible for essential tasks like DNA repair, replication, and maintaining telomeres—the protective caps on DNA that shorten with age. However, exactly how WRN loss leads to faster aging is still not fully understood.

In this study, researchers Pavlo Lazarchuk, Matthew Manh Nguyen, Crina M. Curca, Maria N. Pavlova, Junko Oshima, and Julia M. Sidorova found that beyond its known roles, the WRN gene is also essential for maintaining a specialized structure in the cell nucleus called constitutive heterochromatin (CH). CH is a densely packed form of DNA that keeps certain parts of the genome stable and “switched off,” protecting against unwanted changes. In cells lacking WRN, the CH structure becomes disorganized, leading to DNA instability and accelerating cellular aging.

Another important finding was that WRN loss affects the nuclear envelope, the membrane surrounding DNA, which houses essential proteins like Lamin B1 and Lamin B receptor (LBR). These proteins anchor constitutive heterochromatin (CH) to the nuclear membrane, helping keep DNA compact and stable. Without WRN, this anchoring weakens, and the cell’s internal structure begins to resemble that of aging cells.

“Our study highlights WRN as a contributor to the integrity of CH and points at the altered levels and distribution of LBR as a mediating mechanism.” 

By identifying WRN’s role in organizing the cell’s interior, this study provides a new perspective on age-related genomic instability, where DNA becomes more prone to damage.

In conclusion, this research highlights the importance of stable cell structures in slowing aging, potentially paving the way for future treatments targeting WRN pathways to protect DNA integrity and combat premature aging. This new insight may also inform therapies for age-related diseases.

Read the full paper: DOI: https://doi.org/10.18632/aging.206132

Corresponding Authors: Julia M. Sidorova - julias@uw.edu

Keywords: aging, Werner progeria, heterochromatin, senescence, nuclear lamina, satellite repeats

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About Aging:

The journal Aging aims to promote 1) treatment of age-related diseases by slowing down aging, 2) validation of anti-aging drugs by treating age-related diseases, and 3) prevention of cancer by inhibiting aging. (Cancer and COVID-19 are age-related diseases.)

Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed CentralWeb of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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