Search

U–Pb dating of zircon via laser ablation‐inductively coupled plasma‐mass spectrometry (LA‐ICP‐MS) has become a primary method for determining the age of crystalline rocks and the provenance and maximum depositional age of (meta)sedimentary rocks. Although chemical abrasion has become a standard approach for mitigating Pb loss in zircon dated via high‐resolution thermal ionization mass spectrometry (CA‐TIMS), laser ablation dating is rarely accompanied by chemical abrasion. We evaluate the accuracy of U–Pb dates acquired via LA‐ICP‐MS relative to CA‐TIMS through analysis of a large database of paired analyses from the same zircon crystals. We show that laser ablation 206Pb/238U dates are systematically younger than their CA‐TIMS counterparts, with a greater shift in detrital zircon (−2.0%) versus igneous or metamorphic zircon (−0.9%). Although systematic biases related to “matrix effects” may be a contributing factor, our analysis suggests that unmitigated cryptic Pb loss is likely widespread in laser ablation U–Pb datasets. [ABSTRACT FROM AUTHOR]

The release of paused RNA polymerase II (RNAPII) from promoter-proximal regions is tightly controlled to ensure proper regulation of gene expression. The elongation factor PTEF-b is known to release paused RNAPII via phosphorylation of the RNAPII C-terminal domain by its cyclin-dependent kinase component, CDK9. However, the signal and stress-specific roles of the various RNAPII-associated macromolecular complexes containing PTEF-b/CDK9 are not yet clear. Here, we identify and characterize the CDK9 complex required for transcriptional response to hypoxia. Contrary to previous reports, our data indicate that a CDK9 complex containing BRD4 but not AFF1/4 is essential for this hypoxic stress response. We demonstrate that BRD4 bromodomains (BET) are dispensable for the release of paused RNAPII at hypoxia-activated genes and that BET inhibition by JQ1 is insufficient to impair hypoxic gene response. Mechanistically, we demonstrate that the C-terminal region of BRD4 is required for Polymerase-Associated Factor-1 Complex (PAF1C) recruitment to establish an elongation-competent RNAPII complex at hypoxia-responsive genes. PAF1C disruption using a small-molecule inhibitor (iPAF1C) impairs hypoxia-induced, BRD4-mediated RNAPII release. Together, our results provide insight into potentially targetable mechanisms that control the hypoxia-responsive transcriptional elongation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]