Study Identifies hnRNPM as Guardian of Transcriptome Integrity

Researchers from Baylor College of Medicine have discovered that a protein called hnRNPM helps protect the integrity of the process cells use to make proteins. hnRNPM works by preventing the cell from making mistakes while it is putting together the 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..

"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," explained Chonghui Cheng, co-corresponding author of the study published in Molecular Cell.

The team investigated how cells prevent errors during the splicing process, where exons are joined together to form messenger RNA (mRNA), the blueprint for protein synthesis. They discovered that the human genome contains numerous pseudo splice sites, sequences that resemble actual splice sites but can lead to the inclusion of incorrect exons, a phenomenon known as cryptic splicing.

"The human genome has introns that are significantly longer than exons. These long introns contain numerous small segments, called pseudo splice sites, that are highly similar to the known correct splice sites," said Cheng. "If pseudo splice sites are used instead of the correct splice sites during protein synthesis, the resulting mRNA will contain the wrong instructions—cryptic splicing—that could alter normal cell function."

Through their research, the team unveiled that hnRNPM plays a crucial role in preventing cryptic splicing by binding to introns at regions containing pseudo splice sites, effectively blocking their use during RNA splicing. This mechanism ensures the integrity of the mRNA molecule and the subsequent production of functional proteins.

The team also discovered that in the absence of hnRNPM, cryptic splicing can form double-stranded RNA (dsRNA), which triggers interferon immune responses. "Tumors with low hnRNPM show increased cryptic splicing, interferon immune responses and immune infiltration," Cheng said. "This finding suggests that inhibiting hnRNPM or enhancing the splicing of dsRNA-forming cryptic exons could represent innovative methods to activate immunity in patients with cancer."