DNA repair protein protects against cancer

Australian and Dutch researchers have uncovered a key factor protecting against age-related DNA damage, providing important clues about how the body guards against cancer.

As explained by research leader Dr Edward Chew, from Melbourne’s Walter and Eliza Hall Institute (WEHI), all cancers are caused by changes to a cell’s genome and many cancers become more common with age. But when he and his fellow researchers identified a rare genetic mutation in three patients with an unusual, early-onset form of acute myeloid leukaemia (AML) — typically a disease of older adults — they noticed that these patients were accumulating DNA damage at a higher rate than normal.

“We identified AML samples from three patients that showed unusually high rates of ‘methylation damage’ to the DNA,” Dr Chew said. “DNA methylation has a role in fine-tuning gene activity — but it also makes DNA more susceptible to damage.

“DNA damage occurs constantly and our cells have ways to correct this damage. This is how we safeguard our genome from accumulating damage that puts our cells at risk of cancerous changes.

“When we sequenced the patients’ genomes, we discovered they all carried changes in the same gene, called MBD4. This gene encodes a protein that repairs methylation damage. The loss of [the protein] MBD4 in these patients explained why their cells had not repaired the damage.

“The three patients who lacked MBD4 were predisposed to accumulating high rates of methylation damage — which we believe led to them developing AML as young adults (around 30 years old).”

Dr Edward Chew and Dr Ian Majewski. Image credit: Walter and Eliza Hall Institute Australia.

Methylation damage accumulates as part of normal ageing, but this study — published in the journal Blood — highlighted a particularly strong link with blood cancers, according to co-research leader Dr Ian Majewski.

“We were looking at extreme cases where young individuals had accumulated abnormally high levels of methylation damage, driving the development of AML unusually early in life — it was as though their cells were ageing prematurely,” he said.

“Our research pinpoints methylation damage more generally — even at lower levels — being an important contributor to the development of cancers. An important next step is to understand precisely why blood cells are at risk from this form of DNA damage.”

The discovery relied on recent advances in the fields of genomics and computational biology, with Dr Majewski noting that one of the three AML samples studied was collected in the 1990s — a time when DNA sequencing was still cumbersome and expensive.

“It’s exciting that we’ve now been able to use modern technologies to unravel this mystery, and in the process we’ve gained important new insights into how the ageing process shapes the development of cancers,” Dr Majewski said.

Image caption: As we age, our DNA acquires mutations that can ultimately drive the development of cancer. Image credit: WEHI-TV/Walter and Eliza Hall Institute Australia.