Researchers at Baylor College of Medicine and collaborating institutions have discovered that a protein called hnRNPM helps protect the integrity of the process cells use to make proteins. The protein works by preventing the cell from making mistakes while assembling different components, leading to newly produced proteins. In cancer cells, loss of hnRNPM triggers an interferon immune response, suggesting that this protein may hold clinical promise. The findings appeared in Molecular Cell.
"Synthesizing a protein is like putting together the different parts of a machine. If during the assembly process, parts that do not belong are incorporated into the machine, the final product would not fulfill its intended function, disturbing the normal workings of the cell and potentially leading to disease," said co-corresponding author Dr. Chonghui Cheng, professor at Baylor College of Medicine.
"Despite the many opportunities for such mistakes, cells make proteins highly accurately and precisely. Here we investigated what helps cells maintain the integrity of this vital process."
When a cell needs to synthesize a protein, it begins by getting instructions from the corresponding gene in DNA. This process involves transcribing DNA information into a pre-mRNA molecule composed of exons (coding segments) interspersed with introns (non-coding segments). The pre-mRNA is then spliced to remove introns and form mRNA, which is translated into functional proteins.
The researchers examined how cells prevent errors during exon splicing that could lead to abnormal mRNA molecules by investigating splice sites—the segments marking where exons should be joined.
"The human genome has introns significantly longer than exons containing numerous small segments called pseudo splice sites," said Cheng. "If pseudo splice sites are used instead of correct ones during protein synthesis, resulting mRNA will contain wrong instructions—cryptic splicing—that could alter normal cell function."
They discovered that RNA-binding protein hnRNPM ensures accurate RNA splicing despite many pseudo splice sites by binding preferentially to regions containing these sites and blocking their use during RNA synthesis.
"We found that hnRNPM preferentially binds to introns at regions containing pseudo splice sites," said first author Dr. Rong Zheng. "Their binding prevents or blocks these splice sites when synthesizing RNA molecules, preventing cryptic splicing and maintaining process integrity."
The team also found that without hnRNPM, cryptic splicing can form double-stranded RNA (dsRNA), known to trigger interferon immune responses.
"Tumors with low hnRNPM show increased cryptic splicing, interferon immune responses and immune infiltration," Cheng said. "This finding suggests inhibiting hnRNPM or enhancing dsRNA-forming cryptic exon splicing could represent innovative methods to activate immunity in cancer patients."
Other contributors include Mikayla Dunlap, Georg O.M. Bobkov, Carlos Gonzalez-Figueroa, Khushali J. Patel among others from Baylor College of Medicine, University of California – Los Angeles or Stanford University School of Medicine.
This research was supported in part by grants from NIH (R35-CA209919; R01CA262686; R01AG078950; R35GM131876) and cancer research scholarships from Cancer Prevention Research Institute of Texas Scholars (RR200040; RR160009).
