Cancer cells live under constant siege, generating a steady barrage of DNA damage that many therapies push even further, yet tumors so often survive and come back resistant. New research from Wioletta Czaja, Ph.D., assistant professor in the Department of Genetics, points to one reason why: a chromatin regulator called HELLS that helps cancer cells repair damaged DNA and stay a step ahead of treatment.
The remodelers rewriting cancer's rules
Czaja's focus on HELLS builds on years of work studying the SNF2 family of chromatin remodelers, a subject she has followed since her postdoctoral training. These proteins burn adenosine triphosphate (ATP), the core molecule that stores and moves energy inside all living cells, to control some of the cell's most fundamental processes, including how DNA is transcribed, replicated, and repaired.
“SNF2 remodelers represent a conserved family of proteins using ATP energy to regulate critical cellular processes, including DNA transcription, replication and DNA repair,” Czaja said. “Many members of this family are associated with cancer and therapy resistance, and many members are also emerging as attractive drug targets.”
HELLS stood out for one simple reason: its presence is hard to miss. The protein is overexpressed in 33 different human cancer types and has been tied to numerous cancer-related pathways, yet what it does at the molecular level has remained murky.
Prior work had linked HELLS to the stability of heterochromatin — the densely packaged genome regions that form centromeres and telomeres, essential structural anchors of a chromosome, but HELLS's broader role in genome maintenance was still largely unknown, prompting Czaja's lab to dig deeper.
A housekeeper with a hidden job
For those outside the world of chromatin biology, HELLS can be thought of as a genome housekeeper that works overtime in cells dividing at a rapid pace.
“HELLS is highly expressed in highly proliferating cells, such as cells of the lymphoid tissue, stem cells, and also cancer cells,” Czaja explained.
Its importance becomes even more clear when it's missing. The loss of HELLS causes ICF syndrome, a rare condition marked by immunodeficiency, centromeric instability, and facial abnormalities, and in mouse models, HELLS deficiency has been linked to accelerated aging.
Mechanistically, HELLS behaves much like other members of its protein family, using ATP to reposition nucleosomes and reorganize how DNA is packaged. But Czaja's research has now added a new dimension to that picture.
“Our recent work uncovered a new link between HELLS and cellular responses to DNA alkylation damage,” Czaja said. “We found that HELLS regulates single strand break repair and that it might play a role in DNA replication.”
From basic biology to treatment blueprint
With HELLS's role in DNA repair newly in view, Czaja's lab is working to fill in the mechanistic and clinical details. Three questions are helping guide her efforts:
- How does HELLS promote the repair of single-strand DNA breaks?
- What regions of the genome, like centromeres and telomeres, rely on HELLS for proficient repair?
- Which cancer types rely on HELLS for survival and resistance to therapy?
Answering these questions could reveal not just how HELLS operates, but when and where it matters most, turning a basic biology finding into a framework for which patients might benefit from targeting it.
Not all repair is created equal
For Czaja, the pivotal finding was discovering that HELLS's role isn't generic; it's selective. The protein appears to be specifically tuned to help cells respond to DNA alkylation damage, a type of damage caused by certain widely used chemotherapy drugs.
“HELLS appears to be selectively playing a role in cellular responses to DNA alkylation damage," Czaja said. “Therefore, its targeting might have therapeutic implications in certain cancer types.”
That specificity is what elevates HELLS from an interesting biological observation to a genuine therapeutic lead. It suggests a way to target cancer's defenses without disrupting the same repair machinery healthy cells depend on.
A vulnerability hiding in plain sight
Zooming out, Czaja frames the work as part of a larger story about how cancer survives its own chaos.
“Cancer cells exist in a state of chronic stress,” Czaja said. “Their rapid proliferation and abnormal metabolism generate DNA damage, and many cancer therapies work by increasing that damage even further.”
“Yet tumors can survive and eventually become resistant because they activate protective mechanisms that allow them to repair or tolerate the damage," Czaja explained.
Data from Czaja’s lab suggest HELLS could be one of those protective mechanisms.
“HELLS may provide an additional layer of protection that helps cancer cells survive therapy conditions that would otherwise be lethal,” Czaja said.
That protection appears across many human cancers where HELLS is upregulated, and vanishes when HELLS is removed, exposing a vulnerability. Cancer cells lose ground, becoming less able to repair single-strand breaks and more sensitive to DNA-damaging agents and PARP inhibitors, a class of drugs already used in the clinic.
Turning cancer's strength into its weakness
Looking ahead, Czaja expects new tools to map DNA damage and repair at far finer resolution over the next decade, pinpointing exactly which genomic regions depend on regulators like HELLS, and layering those insights onto genomic and therapeutic response data across tissue and tumor types.
“For HELLS, an important next step will be determining which cancers are most dependent on its DNA-repair functions and whether HELLS inhibition can selectively sensitize those tumors to existing treatments, including alkylating agents and PARP inhibitors,” Czaja explained.
Because HELLS is elevated across multiple cancers, Czaja believes the implications could extend well beyond any single tumor type. She sees this line of inquiry as part of a broader shift taking hold across cancer biology.
“What allows a cancer cell to survive relentless DNA damage?” Czaja asked. “If we can disable those survival mechanisms, we may be able to turn one of cancer's strengths into a therapeutic vulnerability.”
That reframing, turning a tumor's resilience into the very thing that undoes it, is what makes Czaja's work on HELLS worth watching. If the protein really is as central to cancer's survival as the data suggests, disabling it could offer a new way to make existing therapies work better, not by adding more damage, but by stripping away cancer's ability to bounce back from the damage already done.