Study Identifies Mechanism That Helps Prevent Cancer, Neurodegeneration, And Premature Aging

The findings, published successful Nucleic Acids Research, uncover really DNA-protein crosslinks (DPCs) - harmful DNA lesions induced by chemotherapy, formaldehyde, and UV vulnerability - are recognised and surgery down by SPRTN, a cardinal repair enzyme.

The investigation squad discovered a caller region wrong SPRTN that enables it to selectively target DPC lesions, expanding its repair activity 67-fold while leaving surrounding structures unharmed.

Led by Kristijan Ramadan, Toh Kian Chui Distinguished Professor successful Cancer and Stem Cell Biology astatine nan Lee Kong Chian School of Medicine, NTU Singapore and Honorary Senior Researcher astatine nan Department of Oncology, University of Oxford, nan activity has important implications for improving crab therapy and patient aging.

Every clip a compartment divides into two, it must accurately create a transcript of each its DNA, a process that involves nan tight coordination of blase molecular machinery. DNA-protein crosslinks (DPCs) are bulky lesions successful which unwanted proteins connect to DNA, blocking nan process of copying nan cell's DNA.

If near unrepaired, DPCs tin origin neurodegeneration, premature aging, and cancer. Therefore, knowing really these lesions are repaired is important for protecting genome integrity and preventing these conditions.

DPCs tin hap done normal cellular metabolism, arsenic good arsenic vulnerability to chemotherapeutic drugs, UV radiation, and biology agents for illustration formaldehyde. Formaldehyde is simply a Group 1 carcinogen commonly recovered successful family furniture, paint, and aerial pollution, including haze.

SPRTN is simply a captious enzyme that protects cells against DPC lesions. It travels on nan DNA and degrades nan proteins successful nan lesions, which clears nan blockage and enables nan DNA copying process to proceed.

Until now, it was chartless really SPRTN specifically breaks down DPC lesions without damaging functional proteins successful nan cell.

The investigation squad discovered a specialised region wrong SPRTN which drives its activity against DPCs. The region detects chains of ubiquitin - mini tags that connect to different proteins to modify their usability - which DPC lesions person successful abundance.

Recognition of these tags straight guides SPRTN to nan DPC lesions, triggering a accelerated summation successful its activity to break down nan harmful macromolecule attachments.

"In nan absence of ubiquitin chains connected DPCs, SPRTN is slow and inefficient, taking hours to clear nan DNA lesions. But erstwhile nan ubiquitin chains are present, SPRTN's expertise to specifically target DPCs and break them down is enhanced 67-fold, enabling accelerated removal of DPCs, which is captious owed to its domiciled successful nan accelerated repair of DNA," said Prof. Ramadan, who is besides nan Director of nan Cancer Discovery and Regenerative Medicine Programme astatine NTU Singapore's Lee Kong Chian School of Medicine.

Importantly, nan squad showed that longer chains importantly accelerated nan repair process compared to erstwhile only 1 aliases 2 ubiquitin tags were attached to nan DNA lesion. This allows SPRTN to enactment quickly connected DPCs while sparing different proteins that deficiency these tags.

These findings, which show nan value of nan recently discovered SPRTN region for DPC lesion repair, person important implications successful crab therapy and patient aging.

Mutations successful nan SPRTN cistron are known to origin Ruijs-Aalfs syndrome (RJALS), a uncommon information characterised by chromosomal instability, premature aging, and a precocious consequence of early-onset liver cancer. The find of SPRTN's nickname system provides basal insights into our cells' earthy defences and really defects successful DPC repair tin thrust disease.

First writer of nan study, Oxford's postdoctoral interrogator Dr. Wei Song, said: "Our body's expertise to repair DNA harm caused by DPCs has agelong been a mystery. But now that we cognize really nan repair system works, we've laid nan groundwork for processing imaginable ways to fortify nan body's defences against age-related diseases, arsenic good arsenic trim nan broadside effects of crab therapies that harm DNA."

Commenting arsenic an independent expert, Dr. Jens Samol, Senior Consultant successful Medical Oncology, Department of Medical Oncology, Tan Tock Seng Hospital, Singapore, said that nan researchers' study is important arsenic it identified that ubiquitin chains enactment arsenic nan main awesome for SPRTN's accelerated activation and are very apt nan main awesome for SPRTN to specifically target and break down DPCs heavy tagged pinch ubiquitin.

Source:

Journal reference:

Song, W., et al. (2025). The dual ubiquitin binding mode of SPRTN secures accelerated spatiotemporal proteolysis of DNA–protein crosslinks. Nucleic Acids Research. doi.org/10.1093/nar/gkaf638.