RNA polymerase II (pol II) transcribes genes encoding proteins and non-coding small nuclear (sn)RNAs. The carboxy-terminal domain (CTD) of the largest subunit of mammalian RNA polymerase II (pol II), comprising tandem repeats of the heptapeptide consensus tyr1ser2pro3thr4ser5pro6ser7, is required for expression of both gene types. Here, we show that mutation of ser7 to alanine causes a specific defect in snRNA gene expression. We also present evidence that phosphorylation of ser7 facilitates interaction with the snRNA gene-specific Integrator complex. These findings asign a biological function to this amino acid and highlight a gene type-specific requirement for a residue within the CTD heptapeptide, supporting the existence of a CTD code.Human snRNA genes transcribed by pol II, including those encoding U1 and U2 spliceosomal RNAs, have specialized promoters comprising conserved proximal and distal sequence elements (PSE and DSE) (1). Rather than polyadenylation signals, 3′ box elements direct co-transcriptional formation of the primary 3′ end of transcripts (2, 3). The 3′ end of these pre-snRNAs is further processed in the cytoplasm to yields mature non-polyadenylated snRNAs (2). Removal of the CTD of the large subunit of mammalian pol II drastically affects expression of both snRNA and protein-coding genes (2-4). The CTD has a unique structure composed of multiple repeats containing residues that undergo reversible phosphorylation during transcription (5). For example, phosphorylation of ser5 by CDK7 facilitates promoter release and RNA capping, whereas ser2 phosphorylation by CDK9 is associated with processive elongation and 3′ processing (5,6). No role has yet been ascribed to ser7.The mammalian pol II CTD comprises 52 repeats, 25 of which deviate from the consensus at position 7. The mainly consensus repeats 1-25 activate snRNA 3′ processing more effectively than repeats 27-52, which have few serines at position 7 (2). In contrast, both halves of the CTD are equally effective in activating polyadenylation (7). We have tested the requirement for ser7 for expression of snRNA (U2G (2)) and mRNA (pCMV-hnRNPK (8)) templates in 293 cells by introducing mutations into consensus (Con) CTD repeats in an α-amanitin-resistant pol II large subunit (Rpb1) (9) ( Figures 1A, S1A). The large subunit of endogenous pol II is very sensitive to inhibition by α-amanitin, facilitating complementation studies (9). A CTD with at least 25 consensus repeats ((Con) 25 ) was used since this supports * To whom correspondence should be addressed. E-mail: shona.murphy@path.ox.ac.uk. Europe PMC Funders Group Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts efficient production and co-transcriptional 3′ processing of transcripts from snRNA and protein-coding templates, while five CTD repeats (Δ5) do not (2, 4) ( Figure S2A, B).Mutation of ser7 to the non-phospho-acceptor alanine (Ser7A) in a background of 25 repeats reduces the level of properly processed U2G transcripts (Proc) and increases the ratio of ...

Tongue strength was significantly reduced in PwPD and did not differ by medication state. Tongue strength differentiated between PwPD with and without self-reported swallowing symptoms. Therefore, measures of tongue strength and swallowing pressures may serve as clinical indicators for further dysphagia evaluation and may promote early diagnosis and management of dysphagia in PD.

Purpose Dysphagia treatments to address the deterioration of oropharyngeal and respiratory functions in Parkinson's disease (PD) are few and rarely researched in persons with complex medical histories. This research note explored the effects of an intensive exercise-based swallowing program (ISP) that incorporated lingual and respiratory exercises for persons with PD and complex medical history. Method A single-case experiment was conducted across a 4-week ISP of lingual training and expiratory muscle strengthening for 2 participants (67-year-old man and 61-year-old woman). Probes included tongue strength and maximum expiratory pressure. Generalization measures included the Mann Assessment of Swallowing Ability ( Mann, 2002 ), Timed Water Test ( Hughes & Wiles, 1996 ), Repetitive Saliva Swallow Test ( Oguchi et al., 2000 ), Functional Oral Intake Scale ( Crary, Carnaby Mann, & Groher, 2005 ), and Swallowing Quality of Life questionnaire ( McHorney et al., 2002 ). Results Gains occurred in tongue strength and maximum expiratory pressure ( p ≤ .002) with large effect sizes ( d ≥ 1.3) as well as Mann Assessment of Swallowing Ability and Timed Water Test performance. Repetitive Saliva Swallow Test performance and Functional Oral Intake Scale improved for 1 participant, whereas the other maintained function. Swallowing Quality of Life questionnaire remained largely unchanged; however, participants indicated they became more aware of their swallowing difficulties at posttreatment. Conclusions Persons with PD and complex medical history demonstrated increased lingual and expiratory muscle strength following a brief intensive program, which further generalized to select clinical swallowing measures. Findings suggest an overall positive and potentially additive or synergistic effect of an ISP. Future research may refine optimal candidacy and regimens for ISPs, which may help to maximize clinically meaningful returns, especially considering the increased demands of an intensive program.