Abstract
The biological role of the repetitive DNA sequences in the human genome remains an outstanding question. Recent long-read human genome assemblies have allowed us to identify a function for one of these repetitive regions. We have uncovered a tandem array of conserved primate-specific retrogenes encoding the protein Elongin A3 (ELOA3), a homolog of the RNA polymerase II (RNAPII) elongation factor Elongin A (ELOA). Our genomic analysis shows that the ELOA3 gene cluster is conserved among primates and the number of ELOA3 gene repeats is variable in the human population and across primate species. Moreover, the gene cluster has undergone concerted evolution and homogenization within primates. Our biochemical studies show that ELOA3 functions as a promoter-associated RNAPII pause-release elongation factor with distinct biochemical and functional features from its ancestral homolog, ELOA. We propose that the ELOA3 gene cluster has evolved to fulfil a transcriptional regulatory function unique to the primate lineage that can be targeted to regulate cellular hyperproliferation.
| Original language | English (US) |
|---|---|
| Article number | eadj1261 |
| Journal | Science Advances |
| Volume | 9 |
| Issue number | 47 |
| DOIs | |
| State | Published - Nov 2023 |
Funding
We thank S. G. Mackintosh and H. L Douglas at the University of Arkansas for Medical Sciences IDeA National Resource for Quantitative Proteomics for mass spectrometry sample processing and analysis. Funding for the University of Arkansas for Medical Sciences IDeA National Resource for Quantitative Proteomics is provided through a grant from the National Institute of General Medical Sciences (R24GM137786). We thank S. Ganesan for initial help with NGS studies. We thank our collaborator C. Kadoch for providing the SYO-1 cell line. We thank additional colleagues for the kind supply of reagents (see the Materials and Methods). Ape genome assemblies used in this analysis were generated by T2T Primate sequencing consortium and are publicly available from GenomeArk and NCBI. Similarly, all HPRC human genome assemblies are publicly available. This work was supported by National Institutes of Health grant R35CA197569 (A.S.), National Institutes of Health grant R01HL149883 (B.D.S.), National Institutes of Health grant R01HL153122 (B.D.S.), National Institutes of Health grant P01HL154998 (B.D.S.), National Institutes of Health grant P01AG049665 (B.D.S.), National Institutes of Health grant U19AI135964 (B.D.S.), National Institutes of Health grant R01HG002385 (E.E.E.), Howard Hughes Medical Institute Investigator (E.E.E.), and National Institutes of Health grant R24GM137786 (University of Arkansas for Medical Sciences IDeA National Resource for Quantitative Proteomics).
ASJC Scopus subject areas
- General