Cockayne syndrome group A and ferrochelatase finely tune ribosomal gene transcription and its response to UV irradiation

Abstract

CSA and CSB proteins are key players in transcription-coupled nucleotide excision repair (TC-NER) pathway that removes UV-induced DNA lesions from the transcribed strands of expressed genes. Additionally, CS proteins play relevant but still elusive roles in other cellular pathways whose alteration may explain neurodegeneration and progeroid features in Cockayne syndrome (CS). Here we identify a CS-containing chromatin-associated protein complex that modulates rRNA transcription. Besides RNA polymerase I (RNAP1) and specific ribosomal proteins (RPs), the complex includes ferrochelatase (FECH), a well-known mitochondrial enzyme whose deficiency causes erythropoietic protoporphyria (EPP). Impairment of either CSA or FECH functionality leads to reduced RNAP1 occupancy on rDNA promoter that is associated to reduced 47S pre-rRNA transcription. In addition, reduced FECH expression leads to an abnormal accumulation of 18S rRNA that in primary dermal fibroblasts from CS and EPP patients results in opposed rRNA amounts. After cell irradiation with UV light, CSA triggers the dissociation of the CSA–FECH–CSB–RNAP1–RPs complex from the chromatin while it stabilizes its binding to FECH. Besides disclosing a function for FECH within nucleoli, this study sheds light on the still unknown mechanisms through which CSA modulates rRNA transcription.

Ferrochelatase: Mapping the Intersection of Iron and Porphyrin Metabolism in the Mitochondria

“…Ferrochelatase in eukaryotic cells is encoded by the nuclear genome, synthesized in the cytosol with mitochondrial targeting sequence and thereafter translocated to the mitochondria ( Camadro and Labbe, 1988 ; Karr and Dailey, 1988 ). Recently, Lanzafame et al ( Lanzafame et al, 2021 ) revealed that ferrochelatase can also be localized to the nucleus. Here, ferrochelatase forms a complex with CSA–CSB–RNAP1– RPS15–RPS10 to regulate rRNA synthesis and processing ( Lanzafame et al, 2021 ).…”

“…Recently, Lanzafame et al ( Lanzafame et al, 2021 ) revealed that ferrochelatase can also be localized to the nucleus. Here, ferrochelatase forms a complex with CSA–CSB–RNAP1– RPS15–RPS10 to regulate rRNA synthesis and processing ( Lanzafame et al, 2021 ). This finding upends the conventional assumption that ferrochelatase in eukaryotic cells is only localized to the mitochondria.…”

“…Moreover, the above-mentioned report on ferrochelatase function within the nucleus ( Lanzafame et al, 2021 ) elicits more questions on heme metabolism 1) do heme levels affect ferrochelatase rRNA regulatory activities? ; 2) can ferrochelatase synthesize heme in the nucleus?…”

“…To mitigate these effects, these organisms can sense elevated levels of ROS through Fe-S clusters-containing proteins and other molecular machineries and initiate response to this stimulus by regulating the expression of ROS-associated genes ( Dietz, 2014 ; Crack and Le Brun, 2018 ; Rouault, 2019 ; Mariotti et al, 2020 ). Based on the outlined conditions that; 1) Fe-S clusters in metazoan ferrochelatases are sensitive to pH and redox potential (ROS) ( Sellers et al, 1996 ; Shah et al, 2012 ), and 2) ferrochelatase forms a complex with other nuclear proteins to regulate rRNA transcription ( Lanzafame et al, 2021 ), it is possible that ferrochelatase might also act as a redox sensor for signal transduction and gene regulation. To this end, if Fe-S clusters are present in ferrochelatase localized to the nucleus, then, their role in regulating gene expression needs to be explored.…”

A matter of delicate balance: Loss and gain of Cockayne syndrome proteins in premature aging and cancer

“…It has become increasingly clear that some of the features exhibited by CS patients could hardly be attributed to TCR deficiency alone and that CSA and CSB functions extend their roles far beyond of DNA repair. Indeed, studies over the last decades demonstrated that CS proteins participate in other cellular processes: (I) basal and activated transcription as well as in the recovery of RNA synthesis after the massive transcriptional shut down induced upon genotoxic stresses ( Balajee et al, 1997 ; Proietti-De-Santis et al, 2006 ; Kristensen et al, 2013 ; Epanchintsev et al, 2017 ; Lee et al, 2019 ; Epanchintsev et al, 2020 ) (II) Modulation of p53 levels in response to different cellular stresses to re-equilibrate the physiological response in favor of cell survival and proliferation instead of cell cycle arrest and cell death ( Latini et al, 2011 ); (III) Maintenance of mitochondrial homeostasis ( Aamann et al, 2010 ; Berquist and Wilson, 2012 ; Chatre et al, 2015 ) (IV) Regulation of autophagy and lysosomal function ( Scheibye-Knudsen et al, 2012 ; Majora et al, 2018 ) and transcription of RNA polymerase I for ribosomal biogenesis ( Alupei et al, 2018 ; Okur et al, 2020 ; Lanzafame et al, 2021 ) and (V) Regulation of cell division completion through triggering the abscission of the intercellular bridge at the end of cytokinesis ( Paccosi et al, 2020 ). Dysregulated expression of CS proteins has been shown to exhibit differential health outcomes: loss of function by mutations in CS genes invariably leads to complex premature aging phenotypes, and elevated expression of CS proteins is associated with carcinogenesis.…”